Fused bicyclic pyrimidine derivatives

ABSTRACT

A novel fused bicyclic pyrimidine derivative or a salt thereof that acts as a tachykinin receptor antagonist and, in particular, as an NK1 receptor antagonist is represented by the following general formula (1):  
                 
wherein the rings A and B are each a benzene ring having 1 to 3 substituents (any adjacent two of which may be bound to one another to form a ring); the ring C is a nitrogen-containing ring; m is 1 or 2; and n is 2 or 3.

TECHNICAL FIELD

The present invention relates to novel fused bicyclic pyrimidinederivatives and pharmaceutically acceptable salts thereof that act astachykinin receptor antagonists. The present invention also relates tomedical applications of such compounds.

TECHNICAL BACKGROUND

‘Tachykinin’ is a collective term for such neuropeptides as substance P,neurokinin A, and neurokinin B. These tachykinins are known to exhibitvarious physiological activities by binding to corresponding receptorsin a human body (neurokinin 1 (NK1), neurokinin 2 (NK2), and neurokinin3 (NK3), respectively). Of different tachykinins, substance P, asidefrom its role as a neurotransmitter in primary sensory neurons incentral and peripheral nervous systems, brings about variousphysiological effects, such as diuresis, excitation of neurons,increased blood vessel permeability, blood vessel dilation, contractionof smooth muscles, and immune activities. Substance P is also believedto play significant roles in the onset of various pathologicalconditions such as pollakiuria, incontinence, vomiting, inflammation,allergies, respiratory tract disorders, pains, and central nervoussystem disorders. Thus, a need exists for the development of a compoundthat acts as a tachykinin receptor antagonist and, in particular, as anNK1 receptor antagonist and is thus suitable for use as an effectiveprophylactic or therapeutic agent against various pathologicalconditions such as those mentioned above. It is also desirable that sucha compound offer high safety, persistence of efficacy, and otheradvantageous characteristics.

At present, the following compounds are known as NK1 receptorantagonists and are described in the following publications:

-   -   (1) European Patent Application Publication No. EP-A-429366        describes compounds such as the one represented by the following        formula:    -   (2) PCT pamphlet (International Patent Publication) No.        WO91/09844 describes compounds such as the one represented by        the following formula:    -   (3) European Patent Application Publication No. EP-A-532456        describes compounds such as the one represented by the following        formula:    -   (4) European Patent Application Publication No. EP-A-522808        describes compounds such as the one represented by the following        formula:    -   (5) PCT pamphlet (International Patent Publication) No.        WO93/01169 describes compounds such as the one represented by        the following formula:    -   (6) Japanese Patent Laid-Open Publication No. Hei 8-67678        describes a compound represented by the following formula and        salts thereof:        wherein the rings A and B are each a homocyclic or heterocyclic        ring with at least one of the rings A and B being a heterocyclic        ring; the ring C is a benzene ring; R is H or a hydrocarbon        residue; one of X and Y is —NR¹— (where R¹ is H or a hydrocarbon        residue) or —O— and the other is —CO— or —CS—, or one of X and Y        is —N═ and the other is ═CR²— (where R² is H, a halogen, a        hydrocarbon residue, an amino, or hydroxyl group); and n is 1 or        2.    -   (7) Japanese Patent Laid-Open Publication No. Hei 9-104674        describes a compound represented by the following formula:        wherein X is a hydrogen or oxygen atom; Y is a nitrogen or        oxygen atom which may or may not be alkylated or acylated; R¹ is        a hydrogen atom, a lower alkyl group, a lower alkanoyl group, an        alkyl group having a nitrogen atom, a carbamoyl group, a lower        alkylthio group, a lower alkylsulfinyl group, a lower        alkylsulfonyl group, or a (4-phenylpiperadine-1-yl)methyl group;        R² is a hydrogen atom, a lower alkyl group, a lower alkyl group        having a hydroxyl group, a lower alkanoyl group, or a lower        alkoxy group; and the rings A and B are each a substituted or        unsubstituted benzene ring.    -   (8) Japanese Patent Laid-Open Publication No. Hei 9-263585        describes a compound represented by the following formula:        wherein the ring M is a heterocyclic ring in which the        structural moiety —X═Y< is —N═C<, —CO—N<, or —CS—N<; Ra and Rb        may together form the ring A, or Ra and Rb are each        independently a hydrogen atom or a substituent of the ring M;        the rings A and B are each independently a substituted or        unsubstituted homocyclic or heterocyclic ring, provided that at        least one of the rings A and B is a substituted or unsubstituted        heterocyclic ring; the ring C is a substituted or unsubstituted        homocyclic or heterocyclic ring; the ring Z is a substituted or        unsubstituted ring; and n is an integer from 1 to 6.    -   (9) Japanese Patent Laid-Open Publication No. Hei 11-246559        describes a compound represented by the following formula:        wherein X is a nitrogen atom or a CH group; R¹ is a hydrogen        atom, a lower alkyl group, an aryl group, or an aralkyl group;        R² is a hydrogen atom or a lower alkyl group; the rings A and B        are each independently a substituted or unsubstituted benzene        ring; and n is 1 or 2.    -   (10) Japanese Patent Laid-Open Publication No. 2000-139834        describes a compound represented by the following formula:        wherein R¹ and R² are each independently a hydrogen atom or an        C₁ to C₆ alkyl group; R³ is a hydrogen atom, a substituted or        unsubstituted C₁ to C₆ alkylcarbonyl group, a substituted or        unsubstituted C₁ to C₆ alkylsulfonyl group, a substituted or        unsubstituted C₁ to C₆ alkyl group, a substituted or        unsubstituted arylmethyl group or an alkoxycarbonyl group; the        ring A is a homocyclic or heterocyclic ring which may include 1        through 3 independently selected substituents (any adjacent two        of which may be bound to one another to form a ring); the ring B        is a benzene ring which may include 1 through 5 substituents        (any adjacent two of which may be bound to one another to form a        ring); and the ring C is a benzene ring which may include 1        through 3 substituents (any adjacent two of which may be bound        to one another to form a ring).    -   (11) Japanese Patent Laid-Open Publication No. 2000-247957        describes a compound represented by the following formula:        wherein R is a hydrogen atom or the like; R¹ is a hydrogen atom        or the like; R² and R^(2′) are each a hydrogen atom or the like;        R³ is a hydrogen atom or the like; R⁴ is a hydrogen atom or the        like; R⁵ is a hydrogen atom or the like; R⁶ is a hydrogen atom        or the like; X is —C(O)N(R⁵)— or the like; n is an integer from        0 to 4; and m is 1 or 2.    -   (12) PCT pamphlet (International Patent Publication) No.        WO00/50401 describes a compound represented by the following        formula:        wherein R is a hydrogen atom or the like; R¹ is a hydrogen atom        or the like; R² is a hydrogen atom or the like; R³ is a hydrogen        atom or the like; R⁴ is a hydrogen atom or the like; R⁵ is a        hydrogen atom or the like; R⁶ is a hydrogen atom or the like; X        is —C(O)N(R⁵)— or the like; n is an integer from 0 to 4; and m        is 1 or 2.    -   (13) PCT pamphlet (International Patent Publication) No.        WO00/73279 describes a compound represented by the following        formula:        wherein R¹ is a hydrogen atom or the like; R² is a hydrogen atom        or the like; R³ is a hydrogen atom or the like; R⁴ and R^(4′)        are each a hydrogen atom or the like; R⁵ is a lower alkyl group        or the like; n is an integer from 0 to 2; and X is        —C(O)N(R^(4″))— or the like.    -   (14) PCT pamphlet (International Patent Publication) No.        WO00/73278 describes a compound represented by the following        formula:        wherein R¹ is a hydrogen atom or the like; R² is a hydrogen atom        or the like; R³ is a hydrogen atom or the like; R⁴ and R^(4′)        are each a hydrogen atom or the like; R⁵ is a lower alkyl group        or the like; R⁶ is a hydrogen atom or the like; n is an integer        from 0 to 2; and X is —C(O)N(R^(4″))— or the like.

DISCLOSURE OF THE INVENTION

At present, no effective tachykinin antagonists (in particular, NK1receptor antagonists) are known that can serve as prophylactic ortherapeutic agents against the above-described pathological conditionsand at the same time meet requirements for pharmaceutical products,including safety, persistence of efficacy, pharmacokinetics, andpharmacological activities.

It is thus an objective of the present invention to provide a novelcompound that acts as an effective tachykinin receptor antagonist and,in particular, as an NK1 receptor antagonist and can thus serve as aprophylactic or a therapeutic agent against various tachykininreceptor-related pathological conditions, including increased urinaryfrequency, incontinence of urine, vomiting, inflammation, allergies,respiratory tract disorders, pains, and central nervous systemdisorders.

The present inventors have discovered that fused bicyclic pyrimidinederivatives as represented by the following general formula (1), orsalts thereof, can act as effective tachykinin receptor antagonists (inparticular, as NK1 receptor antagonists):(General Formula (1))

wherein the rings A and B are each a benzene ring that may include 1through 3 substituents (any adjacent two of which may be bound to oneanther to form a ring); the ring C is a nitrogen-containing ring; m is 1or 2; and n is 2 or 3. As evidence, the present inventors havedemonstrated in animal experiments that these compounds can effectivelyrelieve dysuria, a tachykinin-mediated disorder. This discovery led thepresent inventors to ultimately complete the present invention.

Accordingly, the present invention provides the followings:

-   -   (I) A fused bicyclic pyrimidine derivative represented by the        following general formula (1), or a salt thereof:        (General Formula (1))        wherein the rings A and B are each a benzene ring, which may        have 1 to 3 substituents (any adjacent two of which may be bound        to one another to form a ring) that are each independently        selected from the group consisting of a halogen atom, a C₁ to C₆        alkyl group, which may be substituted with a halogen atom, and a        C₁ to C₆ alkoxyl group;    -   the ring C is a 5- to 7-membered nitrogen-containing ring, which        may contain, aside from the nitrogen atom, 1 to 3 heteroatoms        selected from the group consisting of a nitrogen atom, a sulfur        atom, and an oxygen atom;    -   the ring C may further contain a substituent selected from the        group consisting of a C₁ to C₆ alkyl group, a hydroxyl group, a        C₁ to C₆ alkoxyl group, a formyl group, a C₁ to C₆ alkylcarbonyl        group, a C₁ to C₆ alkoxycarbonyl group, a carbamoyl group, a        mono- or di-substituted C₁ to C₆ alkylcarbamoyl group, a C₁ to        C₆ alkylsulfonyl group, an amino group, a mono- or        di-substituted C₁ to C₆ alkylamino group, a C₁ to C₆        alkylcarbonylamino group, a C₁ to C₆ alkoxycarbonylamino group,        a C₁ to C₆ alkylsulfonylamino group, an oxo group, a 6-membered        aromatic heterocyclic group, and a substituent represented by        the following formula:        wherein the ring D is a 3- to 7-membered nonaromatic        heterocyclic ring, which may contain, aside from the nitrogen        atom, 1 to 3 heteroatoms selected from the group consisting of a        nitrogen atom, a sulfur atom, and an oxygen atom and may further        contain 1 or 2 oxo-substituted carbon atoms;    -   m is 1 or 2; and    -   n is 2 or 3.    -   (II) The fused bicyclic pyrimidine derivative according to (I)        above represented by the following general formula (1a), or a        salt thereof:        (General Formula (1a))        wherein the ring A is a benzene ring, which may have 1 to 3        substituents (any adjacent two of which may be bound to one        another to form a ring) that are each independently selected        from the group consisting of a halogen atom, a C₁ to C₆ alkyl        group, which may be substituted with a halogen atom, and a C₁ to        C₆ alkoxyl group;    -   the ring C is a 5- to 7-membered nitrogen-containing ring, which        may contain, aside from the nitrogen atom, 1 to 3 heteroatoms        selected from the group consisting of a nitrogen atom, a sulfur        atom, and an oxygen atom;    -   the ring C may further contain a substituent selected from the        group consisting of a (C₁ to C₆ alkyl group, a hydroxyl group, a        C₁ to C₆ alkoxyl group, a formyl group, a C₁ to C₆ alkylcarbonyl        group, a C₁ to C₆ alkoxycarbonyl group, a carbamoyl group, a        mono- or di-substituted C₁ to C₆ alkylcarbamoyl group, a C₁ to        C₆ alkylsulfonyl group, an amino group, a mono- or        di-substituted C₁ to C₆ alkylamino group, a C₁ to C₆        alkylcarbonylamino group, a C₁ to C₆ alkoxycarbonylamino group,        a C₁ to C₆ alkylsulfonylamino group, an oxo group, a 6-membered        aromatic heterocyclic group, and a substituent represented by        the following formula:        wherein the ring D is a 3- to 7-membered nonaromatic        heterocyclic ring, which may contain, aside from the nitrogen        atom, 1 to 3 heteroatoms selected from the group consisting of a        nitrogen atom, a sulfur atom, and an oxygen atom and may further        contain 1 or 2 oxo-substituted carbon atoms; and    -   n is 2 or 3.    -   (III) The fused bicyclic pyrimidine derivative according to (II)        above, or a salt thereof, wherein in the general formula (1a),        the ring C is represented by the following formula:        wherein R¹ is a hydroxyl group, a C₁ to C₆ alkoxy group, a        formyl group, a C₁ to C₆ alkylcarbonyl group, a C₁ to C₆        alkoxycarbonyl group, a carbamoyl group, a mono- or        di-substituted C₁ to C₆ alkylcarbamoyl group, an amino group, a        -mono- or di-substituted C₁ to C₆ alkylamino group, a C₁ to C₆        alkylcarbonylamino group, a C₁ to C₆ alkoxycarbonylamino group,        a C₁ to C₆ alkylsulfonylamino group, an oxo group, a 6-membered        aromatic heterocyclic group, or a substituent represented by the        following formula:        wherein the ring D is a 3- to 7-membered nonaromatic        heterocyclic ring, which may contain, aside from the nitrogen        atom, 1 to 3 heteroatoms selected from the group consisting of a        nitrogen atom, a sulfur atom, and an oxygen atom and may further        contain 1 or 2 oxo-substituted carbon atoms.    -   (IV) The fused bicyclic pyrimidine derivative according to (II)        above, or a salt thereof, wherein in the general formula (1a),        the ring C is represented by the following formula:        wherein X is —O— or —S(O)_(q)—; and q is 0, 1, or 2.    -   (V) The fused bicyclic pyrimidine derivative according to (II)        above, or a salt thereof, wherein in the general formula (1a),        the ring C is a group represented by the following formula:        wherein R² is a hydrogen atom, a C₁ to C₆ alkyl group, a formyl        group, a C₁ to C₆ alkylcarbonyl group, a C₁ to C₆ alkoxycarbonyl        group, a carbamoyl group, a mono- or di-substituted C₁ to C₆        alkylcarbamoyl group or a C₁ to C₆ alkylsulfonyl group; and r is        1 or 2.    -   (VI) The fused bicyclic pyrimidine derivative according to (II)        above, or a salt thereof, wherein in the general formula (1a),        the ring C is represented by the following formula:        wherein R^(2′) is an acetyl group or a methylsulfonyl group; and        r is 1 or 2.    -   (VII) The fused bicyclic pyrimidine derivative according to (II)        above, or a salt thereof, wherein in the general formula (1a)        above, the ring C is represented by the following formula:    -   (VIII) The fused bicyclic pyrimidine derivative according        to (VII) above, or a salt thereof, wherein in the general        formula (1a) above, n is 3.    -   (IX) The compound according to (I) above, wherein the compound        represented by the general formula (1) is        9-(4-acetylpiperazine-1-yl)-5-[3,5-bis(trifluoromethyl)benzyl]-7-(2-methylphenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine.    -   (X) The compound according to (I) above, wherein the compound        represented by the general formula (1) is        5-[3,5-bis(trifluoromethyl)benzyl]-9-(1,1-dioxothiomorpholine-4-yl)-7-(2-methylphenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine.    -   (XI) The compound according to (I) above, wherein the compound        represented by the general formula (1) is        9-(4-acetylhomopiperazine-1-yl)-5-[3,5-bis(trifluoromethyl)benzyl]-7-(2-methylphenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine.    -   (XII) The compound according to (I) above, wherein the compound        represented by the general formula (1) is        5-[3,5-bis(trifluoromethyl)benzyl]-7-(2-methylphenyl)-9-(4-methylpiperazine-1-yl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine.    -   (XIII) A tachykinin receptor antagonist containing as an active        ingredient the fused bicyclic pyrimidine derivative according to        any one of (I) through (XII) above, or a salt thereof.    -   (XIV) An NK1 receptor antagonist containing as an active        ingredient the fused bicyclic pyrimidine derivative according to        any one of (I) through (XII) above, or a salt thereof.    -   (XV) A prophylactic or therapeutic agent for dysuria, including        defective bladder functions such as increased urinary frequency        and incontinence of urine, containing as an active ingredient        the fused bicyclic pyrimidine derivative according to any of (I)        through (XII) above, or a salt thereof.    -   (XVI) A prophylactic or therapeutic agent for disorders of        digestive tract such as ulcerative colitis and Crohn's disease,        containing as an active ingredient the fused bicyclic pyrimidine        derivative according to any of (I) through (XII) above, or a        salt thereof.    -   (XVII) A prophylactic or therapeutic agent for vomiting induced        by exposure to X-ray, chemotherapy, pregnancy, migraine,        postoperative pains, decreased gastrointestinal motility, and        side effects of drugs, containing as an active ingredient the        fused bicyclic pyrimidine derivative according to any of (I)        through (XII) above, or a salt thereof.    -   (XVIII) A therapeutic agent for treating conditions, such as        asthma, coughing, ache, migraine, tooth pain, and rheumatoid        arthritis, containing as an active ingredient the fused bicyclic        pyrimidine derivative according to any of (I) through (XII)        above, or a salt thereof.

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention will now be described in detail.

Rings A and B

In the general formula (1), the rings A and B each independentlyrepresent a benzene ring, which may include 1 to 3 substituents (anyadjacent two of which substituents may be bound to one another to form aring). The substituents on each of the rings A and B may be positionedat any possible position with the number of the substituents on eachring varying from about 1 to 3. Any adjacent two of these substituentsmay be bound to each other to form a ring. Examples of the substituentson the rings A and B include halogen atoms, C₁ to C₆ alkyl groups, whichmay be substituted with halogen atoms, and C₁ to C₆ alkoxyl groups.

Examples of the halogen atoms include fluorine atom, chlorine atom,bromine atom, and iodine atom.

Examples of the “C₁ to C₆ alkyl groups that may be substituted withhalogen atoms” include methyl group, ethyl group, propyl group,isopropyl group, isobutyl group, sec-butyl group, tert-butyl group,fluoromethyl group, chloromethyl group, bromomethyl group, iodomethylgroup, 1-fluoroethyl group, 1-chloroethyl group, 2-chloroethyl group,difluoromethyl group, trifluoromethyl group, trichloromethyl group, and2,2,2-trifluoroethyl group.

Examples of the “C₁ to C₆ alkoxyl groups” include methoxy group, ethoxygroup, propoxy group, isopropoxy group, isobutoxy group, sec-butoxygroup, and tert-butoxy group.

Examples of the “rings in which two adjacent substituents are bound toeach other to form a ring” include the followings:

Ring A

Preferred examples of the ring A are those represented by the followingformulae:

wherein R³, R⁴, and R⁵ are each independently a fluorine atom, achlorine atom, a methyl group, an ethyl group, a trifluoromethyl group,or a methoxy group.

Particularly preferred examples of the ring A are those represented bythe following formulae:

Ring B

Preferred examples of the ring B are those represented by the followingformulae:

wherein R⁶, R⁷, and R⁸ are each independently a fluorine atom, achlorine atom, a methyl group, an ethyl group, a trifluoromethyl group,or a methoxy group.

Particularly preferred examples of the ring B are those represented bythe following formulae:

Ring C

The ring C is a 5- to 7-membered nitrogen-containing ring that may besubstituted and may contain, aside from the nitrogen atom, 1 to 3heteroatoms selected from the group consisting of a nitrogen atom, asulfur atom, and an oxygen atom. Examples of “5- to 7-memberednitrogen-containing rings that may contain, aside from a nitrogen atom,1 to 3 heteroatoms selected from the group consisting of a nitrogenatom, a sulfur atom, and an oxygen atom” include 5-membered aromaticheterocyclic rings that may contain, aside from a nitrogen atom, 1 to 3heteroatoms selected from the group consisting of a nitrogen atom, asulfur atom, and an oxygen atom (such as pyrrole, imidazole, pyrazole,triazole, and tetrazole rings) and 5- to 7-membered nonaromaticheterocyclic rings that may contain, aside from a nitrogen atom, 1 to 3heteroatoms selected from the group consisting of a nitrogen atom, asulfur atom, and an oxygen atom (such as tetrahydropyridine,dihydropyridine, tetrahydropyrazine, tetrahydropyrimidine,tetrahydropyridazine, dihydropyrrole, dihydroimidazole, dihydropyrazole,dihydrooxazole, dihydroisooxazole, piperidine, piperazine,hexahydropyrimidine, hexahydropyridazine, morpholine, thiomorpholine,homopiperidine, homopiperazine, pyrrolidine, imidazolidine,pyrazolidine, tetrahydrooxazole, tetrahydroisooxazole rings.).

Examples of “optional substituents on the ring C” include a C₁ to C₆alkyl group, a hydroxyl group, a C₁ to C₆ alkoxy group, a formyl group,a C₁ to C₆ alkylcarbonyl group, a C₁ to C₆ alkoxycarbonyl group, acarbamoyl group, a mono- or di-substituted C₁ to C₆ alkylcarbamoylgroup, a C₁ to C₆ alkylsulfonyl group, an amino group, a mono- ordi-substituted C₁ to C₆ alkylamino group, a C₁ to C₆ alkylcarbonylaminogroup, a C₁ to C₆ alkoxycarbonylamino group, a C₁ to C₆alkylsulfonylamino group, an oxo group, a 6-membered aromaticheterocyclic group, and a group represented by the following formula:

(wherein the ring D is a 3- to 7-membered nonaromatic heterocyclic ringthat may contain, aside from the nitrogen atom, 1 to 3 heteroatomsselected from the group consisting of a nitrogen atom, a sulfur atom,and an oxygen atom and may further contain 1 or 2 oxo-substituted carbonatoms).

Examples of the “C₁ to C₆ alkyl group” include methyl group, ethylgroup, propyl group, isopropyl group, isobutyl group, sec-butyl group,and tert-butyl group.

Examples of the “C₁ to C₆ alkoxy group” include methoxy group, ethoxygroup, propoxy group, isopropoxy group, isobutoxy group, sec-butoxygroup, and tert-butoxy group.

Examples of the “C₁ to C₆ alkylcarbonyl group” include acetyl group,propionyl group, and butyryl group.

Examples of the “C₁ to C₆ alkoxycarbonyl group” include methoxycarbonylgroup, ethoxycarbonyl group, isopropoxycarbonyl group, andt-butoxycarbonyl group.

Examples of the “mono- or di-substituted C₁ to C₆ alkylcarbamoyl group”include methylcarbamoyl group, ethylcarbamoyl group, propylcarbamoylgroup, isopropylcarbamoyl group, t-butylcarbamoyl group, hexylcarbamoylgroup, dimethylcarbamoyl group, diethylcarbamoyl group,dipropylcarbamoyl group, diisopropylcarbamoyl group, dibutylcarbamoylgroup, and dihexylcarbamoyl group.

Examples of the “C₁ to C₆ alkylsulfonyl group” include methylsulfonylgroup, ethylsulfonyl group, and propylsulfonyl group.

Examples of the “mono- or di-substituted C₁ to C₆ alkylamino group”include methylamino group, ethylamino group, propylamino group,isopropylamino group, t-butylamino group, hexylamino group,dimethylamino group, diethylamino group, dipropylamino group,diisopropylamino group, dibutylamino group, and dihexylamino group.

Examples of the “C₁ to C₆ alkylcarbonylamino group” include acetylaminogroup, propionylamino group, and butyrylamino group.

Examples of the “C₁ to C₆ alkoxycarbonylamino group” includemethoxycarbonylamino group, ethoxycarbonylamino group,t-butoxycarbonylamino group, and hexyloxycarbonylamino group.

Examples of the “C₁ to C₆ alkylsulfonylamino group” includemethylsulfonylamino group, and ethylsulfonylamino group.

Examples of the “6-membered aromatic heterocyclic group” include pyridylgroup, pyrazyl group, pyrimidyl group, and pyridazinyl group.

Examples of the “functional group represented by the following formula:

(wherein the ring D is a 3- to 7-membered nonaromatic heterocyclic ringthat may contain, aside from the nitrogen atom, 1 to 3 heteroatomsselected from the group consisting of a nitrogen atom, a sulfur atom,and an oxygen atom and may further contain 1 or 2 oxo-substituted carbonatoms)” include azetidino group, pyrrolidino group, piperidino group,morpholino group, thiomorpholino group, piperazino group,4-methylpiperazino group, homopiperazino group, 2-oxopyrrolidino group,3-oxomorpholino group, and 2-oxomorpholino group.

Preferred examples of the ring C include those represented by thefollowing formulae:

Of these, particularly preferred are those represented by the followingformulae:

Of these, more preferred are those represented by the followingformulae:

m

-   -   m is 1 or 2, and preferably 1.        n    -   n is 2 or 3, and preferably 3.

Preferred examples of the compounds of the present invention include5-[3,5-bis(trifluoromethyl)benzyl]-9-(morpholine-4-yl)-6-oxo-7-phenyl-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine;5-[3,5-bis(trifluoromethyl)benzyl]-7-(2-fluorophenyl)-9-(morpholine-4-yl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine;5-[3,5-bis(trifluoromethyl)benzyl]-7-(2-methylphenyl)-9-(morpholine-4-yl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine;5-[3,5-bis(trifluoromethyl)benzyl]-7-(2-chlorophenyl)-9-(morpholine-4-yl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine;5-[3,5-bis(trifluoromethyl)benzyl]-7-(4-fluorophenyl)-9-(morpholine-4-yl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine;5-[3,5-bis(trifluoromethyl)benzyl]-7-(2,4-difluorophenyl)-9-(morpholine-4-yl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine;5-[3,5-bis(trifluoromethyl)benzyl]-7-(4-methoxyphenyl)-9-(morpholine-4-yl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine;5-[3,5-bis(trifluoromethyl)benzyl]-7-(2,4-dimethoxyphenyl)-9-(morpholine-4-yl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine;5-[3,5-bis(trifluoromethyl)benzyl]-7-[4-(dimethylamino)phenyl]-9-(morpholine-4-yl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine;5-[3,5-bis(trifluoromethyl)benzyl]-1-(2-methoxyphenyl)-9-(morpholine-4-yl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine;5-[3,5-bis(trifluoromethyl)benzyl]-6-oxo-7-phenyl-9-[4-(pyrrolidine-1-yl)piperidine-1-yl]-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine;5-[3,5-bis(trifluoromethyl)benzyl]-7-(2-methylphenyl)-6-oxo-9-[4-(pyrrolidine-1-yl)piperidine-1-yl]-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine;5-[3,5-bis(trifluoromethyl)benzyl]-7-(4-fluorophenyl)-6-oxo-9-[4-(pyrrolidine-1-yl)piperidine-1-yl]-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine;5-[3,5-bis(trifluoromethyl)benzyl]-7-(2-methylphenyl)-6-oxo-9-[4-(pyrimidine-2-yl)piperazine-1-yl]-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine;5-[3,5-bis(trifluoromethyl)benzyl]-7-(2-methylphenyl)-6-oxo-9-[4-(pyridine-2-yl)piperazine-1-yl]-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine;9-(4-acetylpiperazine-1-yl)-5-[3,5-bis(trifluoromethyl)benzyl]-7-(2-methylphenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine;5-[3,5-bis(trifluoromethyl)benzyl]-9-(4-formylpiperazine-1-yl)-7-(2-methylphenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine;5-[3,5-bis(trifluoromethyl)benzyl]-9-(imidazole-1-yl)-7-(2-methylphenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine;5-[3,5-bis(trifluoromethyl)benzyl]-7-(2-methylphenyl)-6-oxo-9-(1,2,4-tetrazole-1-yl)-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine;5-[3,5-bis(trifluoromethyl)benzyl]-9-(1,1-dioxothiomorpholine-4-yl)-7-(2-methylphenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine;5-[3,5-bis(trifluoromethyl)benzyl]-9-[3-(ethoxycarbonyl)piperidine-1-yl]-7-(2-methylphenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine;5-[3,5-bis(trifluoromethyl)benzyl]-9-[4-(ethoxycarbonyl)piperidine-1-yl]-7-(2-methylphenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine;5-[3,5-bis(trifluoromethyl)benzyl]-9-(3-carbamoylpiperidine-1-yl)-7-(2-methylphenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine;5-[3,5-bis(trifluoromethyl)benzyl]-9-(4-carbamoylpiperidine-1-yl)-7-(2-methylphenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine;5-[3,5-bis(trifluoromethyl)benzyl]-9-[3-(dimethylamino)pyrrolidine-1-yl]-7-(2-methylphenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine;5-[3,5-bis(trifluoromethyl)benzyl]-9-(4-methylhomopiperazine-1-yl)-7-(2-methylphenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine;5-[3,5-bis(trifluoromethyl)benzyl]-9-[3-(acetylamino)pyrrolidine-1-yl]-7-(2-methylphenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine;9-(4-acetylpiperazine-1-yl)-5-[3,5-bis(trifluoromethyl)benzyl]-7-(4-fluorophenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine;9-(4-acetylpiperazine-1-yl)-5-[3,5-bis(trifluoromethyl)benzyl]-7-(2-methoxyphenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine;9-(4-acetylpiperazine-1-yl)-5-[3,5-bis(trifluoromethyl)benzyl]-6-oxo-7-phenyl-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine;9-(4-acetylpiperazine-1-yl)-5-[3,5-bis(trifluoromethyl)benzyl]-7-(4-fluoro-2-methylphenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine;8-(4-acetylpiperazine-1-yl)-4-[3,5-bis(trifluoromethyl)benzyl]-6-(2-methylphenyl)-5-oxo-2,3,4,5-tetrahydropyrimido[5,4-f][1,4]oxazepine;5-[3,5-bis(trifluoromethyl)benzyl]-7-(2-methylphenyl)-6-oxo-9-[4-(2-oxopyrrolidine-1-yl)piperidine-1-yl]-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine;5-[3,5-bis(trifluoromethyl)benzyl]-7-(2-methylphenyl)-9-[4-(morpholine-4-yl)piperidine-1-yl]-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine;5-[3,5-bis(trifluoromethyl)benzyl]-9-[4-(dimethylamino)piperidine-1-yl]-7-(2-methylphenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine;5-[3,5-bis(trifluoromethyl)benzyl]-7-(2-methylphenyl)-6-oxo-9-[4-(piperidine-1-yl)piperidine-1-yl]-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine;9-[4-(acetylamino)piperidine-1-yl]-5-(3,5-bis(trifluoromethyl)benzyl]-7-(2-methylphenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine;5-[3,5-bis(trifluoromethyl)benzyl]-9-[4-(methylsulfonylamino)piperidine-1-yl]-7-(2-methylphenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine;5-[3,5-bis(trifluoromethyl)benzyl]-9-[4-(methylsulfonyl)piperazine-1-yl]-7-(2-methylphenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine;5-[3,5-bis(trifluoromethyl)benzyl]-9-[4-(methylsulfonyl)homopiperazine-1-yl]-7-(2-methylphenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine;9-(4-acetylhomopiperazine-1-yl)-5-[3,5-bis(trifluoromethyl)benzyl]-7-(2-methylphenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine;9-[3-(acetylamino)-3-methylpyrrolidine-1-yl]-5-[3,5-bis(trifluoromethyl)benzyl]-7-(2-methylphenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine;5-[3,5-bis(trifluoromethyl)benzyl]-9-(1,1-dioxothiomorpholine-4-yl)-7-(2-methoxyphenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine;and5-[3,5-bis(trifluoromethyl)benzyl]-7-(2-methylphenyl)-9-(4-methylpiperazine-1-yl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine.

Salts

Examples of pharmaceutically acceptable salts of the compounds of thepresent invention include those formed with inorganic acids, such ashydrochloric acid, hydrobromic acid, sulfuric acid, and nitric acid, andthose formed with organic acids, such as acetic acid, maleic acid,fumaric acid, succinic acid, lactic acid, malic acid, tartaric acid,citric acid, methanesulfonic acid, p-toluenesulfonic acid, salicylicacid, stearic acid, and palmitic acid.

The compounds of the present invention or salts thereof may also existin the form of hydrates or solvates. The present invention encompassesany hydrates or solvates formed by the fused bicyclic pyrimidinederivatives of the general formula (1), including the preferredcompounds specifically mentioned above, or salts thereof. Examples ofthe solvents that can form solvates include methanol, ethanol,isopropanol, acetone, ethyl acetate, methylene chloride, anddiisopropylether.

Aside from racemic mixtures, the compounds of the present invention orsalts thereof may be provided in the form of optically active forms,stereoisomers, or atrop isomers.

Various synthetic techniques may be used to produce the compounds of thepresent invention. One commonly used production process of the compoundsof the present invention or salts thereof is described below.

(Step 1)

In this step, a carbonyl group is introduced into a compound (a)(wherein R⁹ is a leaving group that is eliminated later in Step 5 of theprocess, such as a halogen atom, a C₁ to C₆ alkylthio group, an arylthiogroup, a C₁ to C₆ alkylsulfonyl group, or an arylsulfonyl group, or R⁹is the ring C (the ring C is as described above)) to generate a compound(b) (wherein R⁹ is as described above; R¹⁰ is a hydroxyl group, ahalogen atom, 1-imidazolyl group, 4-nitrophenoxy group, imidoyloxysuccinate group, a C₁ to C₆ alkoxyl group, or a benzyloxy group). Inthis process, the compound (b) is generated by first treating thecompound (a) with a base and then reacting the product with a compoundthat serve as a source of carbonyl group. The base for use in thisprocess may be a bulky base, such as lithium diisopropylamide. Theprocess is generally carried out at a temperature of −100° C. to 20° C.,and preferably at a temperature of −100° C. to −50° C. The compound thatserves as the source of carbonyl group for use in this process may be ahalide of a carboxylic acid, an imidazolide of a carboxylic acid, anactive ester of a carboxylic acid, an acid hydride, an orthoester orcarbon dioxide. When R¹⁰ is a hydroxyl group, the compound (a) is firsttreated with the above-described base and carbon dioxide is used as thesource of carbonyl group. The process is terminated using a proper acid(e.g., hydrochloric acid).

(Step 2)

In this step, the compound (b) (wherein R⁹ and R¹⁰ are as describedabove) and the compound (c) (wherein the ring B is as described above)are allowed to undergo condensation to generate a compound (d) (whereinR⁹ and the ring B are as described above). When R¹⁰ is a hydroxyl group,a suitable condensation agent for use in the condensation reaction inthis step may be dicyclohexylcarbodiimide (DCC),3-ethyl-1-(3-dimethylaminopropyl)carbodimide hydrochloride (EDCI), ordimethylimidazolinium chloride (DMC). These condensation agents may beadded in the form of a solid product or a solution in a proper solvent.A base may be used in the condensation reaction, including alkalicarbonates, such as sodium hydrogen carbonate, or potassium carbonate,and tertially amines, such as triethylamine, diisopropylethylamine,N-methylmorpholine, diazabicyclo[5.4.0]-7-undecene, pyridine,4-dimethylaminopyridine, or 1,8-bis(dimethylamino)naphthalene. Thesolvent for use in the condensation reaction may be any inert solventthat does not take part in the reaction, includingN,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide,acetonitrile, tetrahydrofuran, dioxane, ethyl ether, dimethoxyethane,ethylacetate, and dichloromethane. The condensation reaction may becarried out at −20° C. to 80° C. When the compound (b) for use in thecondensation reaction in this step is any of a halide of a carboxylicacid, an imidazolide of a carboxylic acid, or an active ester of acarboxylic acid, in which R¹⁰ is a halogen atom, a 1-imidazolyl group, a4-nitrophenoxy group or an imidoyloxy succinate group, the reaction canbe carried out by allowing the reactants to react in the presence orabsence of an organic base, such as triethylamine,diisopropylethylamine, pyridine or 4-dimethylaminopyridine, or aninorganic base, such as sodium hydrogen carbonate or potassiumcarbonate, in a solvent, such as N,N-dimethylformamide,N,N-dimethylacetamide, dimethylsulfoxide, acetonitrile, tetrahydrofuran,dioxane, ethyl ether, dimethoxyethane, ethylacetate, toluene ordichloromethane, at −20° C. to 80° C. for 30 min. to 48 hours. When R¹⁰is a C₁ to C₆ ester residue such as an alkoxyl group and a benzyloxygroup in the condensation reaction in this step, the reaction can becarried out by allowing the reactants to react in the presence orabsence of trimethylaluminum or tetraisopropoxytitanium or in thepresence or absence of an acidic or a basic catalyst, such asp-toluenesulfonic acid, sodium methoxide, potassium t-butoxide, orsodium hydride, in a solvent, such as N,N-dimethylformamide,N,N-dimethylacetamide, dimethylsulfoxide, acetonitrile, tetrahydrofuran,dioxane, toluene, xylene, mesitylene, pyridine, quinoline, ordichloromethane, at 15° C. to 150° C. for 30 min. to 48 hours.

(Step 3)

In this step, the compound (d) (wherein R⁹ and the ring B are asdescribed above) is cyclized to generate a compound (e) (wherein R⁹ andthe ring B are as described above). The step may be carried out byallowing the cyclization to take place in the presence or absence of anorganic base, such as sodium-tert-butoxide or potassium-tert-butoxide,or an inorganic base, such as sodium hydride, potassium carbonate,sodium carbonate, cesium carbonate or sodium acetate, in a solvent, suchas N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide,acetonitrile, tetrahydrofuran, dioxane, toluene, xylene, mesitylene,pyridine, quinoline, or dichloromethane, at 0° C. to 150° C. for 30 min.to 48 hours.

(Step 4)

In this step, the compound (e) (wherein R⁹ and the ring B are asdescribed above) and a compound (f) (wherein the ring A is as describedabove, Y is a halogen atom, OSO₂R¹¹ (wherein R¹¹ is a C₁ to C₆ alkylgroup, which may be substituted with halogen atoms), B(R¹²)₂ (whereinthe two R¹² substituents are each independently a hydroxyl group, a C₁to C₆ alkyl group or a C₁ to C₆ alkoxyl group, or R¹² substituents maybe bound to each other to form a ring), Li, MgBr, or ZnCl) are allowedto undergo either a cross-coupling reaction in the presence of atransitional metal catalyst, such as a palladium or nickel complex, or aGrignard reaction to generate a compound (g) (wherein R⁹ and the rings Aand B are as described above). Preferably, the process is carried out byusing an inert solvent that does not take part in the process. Examplesof the solvent include N,N-dimethylformamide, N,N-dimethylacetamide,dimethylsulfoxide, acetonitrile, tetrahydrofuran, dioxane,dichloromethane, toluene, ethanol or water. These solvents may be usedindividually or may be mixed with one another in any proportion.Examples of the palladium complexes for use in the process includepalladium chloride, palladium acetate, acetylacetonato palladium, andtetrakis(triphenylphosphine)palladium. Examples of the nickel complexesfor use in the process include bis(acetylacetonato)nickel,bis(1,5-cyclooctadiene)nickel, and tetrakis(triphenylphosphine)nickel.Each of these palladium or nickel complexes is used in an amount of0.001 to 1 equivalent, preferably in an amount of 0.01 to 0.1equivalents, with respect to the compound (e). When it is desired to usea ligand for the palladium or nickel complex in the process, the ligandmay be triphenylphosphine, tri-o-tolylphosphine, tri-2-furylphosphine,1,2-bis(diphenylphosphino)ethane, 1,1′-bis(diphenylphosphino)ferrocene,or 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl. Each of these ligands isused in an amount of 0.2 to 5 equivalents, preferably in an amount of0.3 to 3 equivalents, with respect to the palladium or nickel complex.Preferably, the process is carried out in the presence of a proper base.Among such bases are organic bases, including triethylamine,tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine,lutidine, and collidine, and inorganic bases, including sodium hydrogencarbonate, sodium carbonate, potassium carbonate, calcium carbonate,cesium carbonate, and tripotassium phosphate. Each of these bases isused in an amount of 1 to 20 equivalents, preferably in an amount of 2to 10 equivalents, with respect to the compound (e). The cross-couplingreaction in this step is carried out by allowing the reactants toundergo the reaction at 15 to 150° C., preferably at 50 to 120° C., for30 min. to 24 hours.

(Step 5)

In this step, the compound (g) (wherein R⁹ and the rings A and B are asdescribed above) is reacted with a compound (h) to generate a compound(i) (wherein R⁹ and the rings A and B are as described above). (Thisstep is omitted when R⁹ is the ring C.) The process can be carried outby using the compound (h) in an amount of 1 to 20 equivalents withrespect to the compound (g) and allowing the reaction to proceed in thepresence or absence of a base at 80 to 200° C., preferably at 100 to150° C., for 30 min. to 24 hours. A base may preferably be used,including organic bases, such as trimethylamine, tributylamine,diisopropylethylamine, N-methylmorpholine, pyridine, lutidine,collidine, and N,N-dimethylaniline, and inorganic bases, such as sodiumhydrogen carbonate, sodium carbonate, potassium carbonate, calciumcarbonate, cesium carbonate, and tripotassium phosphate. When it isdesired to use a solvent, such a solvent may be any inert solvent thatdoes not take part in the reaction, including N,N-dimethylformamide,N,N-dimethylacetamide, sulfolane, acetonitrile, tetrahydrofuran,dioxane, xylene, toluene, ethanol, or water.

The compounds (1) of the present invention can be isolated/purified byordinary means (for example, extraction, recrystallization,distillation, and chromatography). When the resulting compounds tend toform salts, such salts can be produced by ordinary techniques orequivalent techniques (for example, neutralization).

The compounds (1) of the present invention or salts thereof act astachykinin receptor antagonists and, in particular, as NK1 receptorantagonists and are thus useful as:

-   -   prophylactic or therapeutic agents for dysuria, including        defective bladder functions such as increased urinary frequency        and incontinence of urine;    -   prophylactic or therapeutic agents for disorders of digestive        tract such as ulcerative colitis and Crohn's disease;    -   prophylactic or therapeutic agents for vomiting induced by        exposure to X-ray, chemotherapy, pregnancy, migraine,        postoperative pains, decreased gastrointestinal motility, and        side effects of drugs;    -   prophylactic or therapeutic agents for vomiting induced by        exposure to X-ray, chemotherapy, pregnancy, migraine,        postoperative pains, decreased gastrointestinal motility, and        side effects of drugs; and    -   therapeutic agents for asthma, coughing, ache, migraine, tooth        pain, rheumatoid arthritis and other conditions.

The compounds (1) of the present invention or salts thereof may be usedindividually, or they may be formed into pharmaceutical compositionsalong with one or more pharmaceutically acceptable adjuvants.Specifically, the compounds of the present invention may be mixed withpharmaceutically acceptable carriers, excipients (such as starch,lactose, calcium phosphate, and calcium carbonate), lubricants (such asmagnesium stearate, calcium stearate, talc, and stearic acid), binders(such as starch, cellulose crystals, carboxymethylcellulose, gum Arabic,polyvinylpyrrolidone, and alginic acid), disintegrating agents (such astalc, carboxymethylcellulose, and calcium), and diluents (such asphysiological saline, and aqueous solutions of glucose, mannitol andlactose). Using ordinary techniques, the compounds of the presentinvention may be prepared as tablets, capsules, granules, powders, finegranules, ampules, or injections for oral or parenteral administration.While the dosage of the compounds (1) of the present invention or saltsthereof may vary depending on the type of salt, route of administration,and age and conditions of patients, a typical dose for humans and othermammals, for example, is in the range of 0.0001 to 300 mg/kg/day asmeasured by the amount of the compounds (1) of the present invention orsalts thereof. The compounds (1) or salts thereof may be administered ina single dose or several doses each day.

EXAMPLES

The present invention will now be described in detail with reference toExamples, Reference Examples, and Test Examples, as will an exemplaryproduction process of a starting material of the compounds (1) of thepresent invention, which is also a novel compound. It should beappreciated that the compounds of the present invention are not limitedto those described in the following examples and may be modified withoutdeparting from the scope and the spirit of the invention.

Reference Example 1

2-bromoethylether (3.65 g), potassium carbonate (8.29 g), andN,N-dimethylformamide (75 mL) were added to2-amino-4,6-dichloropyrimidine (2.46 g), and the mixture was refluxedfor 3 hours while heated. Subsequently, the reaction mixture was dilutedwith ethyl acetate, was washed with water, and was dried over anhydroussodium sulfate. The solvent was removed and the resulting residue waspurified on a silica gel column chromatography (hexane:ethylacetate=5:1) to obtain 4,6-dichloro-2-(morpholine-4-yl)pyrimidine (985mg, 28%).

MS (EI) m/z:233(M⁺)

HRMS (EI): Calcd for C₈H₉Cl₂N₃O: 233.0123; found:233.0152

Reference Example 2

4 mol/L hydrogen chloride-dioxane (3.3 mL) was added to4-(pyrrolidine-1-yl)piperidine (2.01 g) and the mixture was stirred atroom temperature for 1 hour. Cyanamid (1.10 g) and n-butanol (20 mL)were then added and the mixture was stirred at 120° C. for 3 hours. Thesolvent was removed to obtain4-(pyrrolidine-1-yl)piperidine-1-carboxyamidine hydrochloride (3.00 g,99%). Subsequently, sodium metal (550 mg) is dissolved in ethanol (30mL), and the resulting 4-(pyrrolidine-1-yl)piperidine-1-carboxyamidinehydrochloride (2.80 g) was added along with diethyl malonate (1.93 g)thereto. The mixture was stirred for 5 hours while heated. The mixturewas then allowed to cool and 3 mol/L hydrogen chloride-ethyl acetate (5mL) was added to adjust pH to 1. The solvent was removed to obtain aresidue. Phosphorus oxychloride (70 mL) was then added to this residueand the mixture was refluxed for 2 hours while heated. Following removalof the solvent, water and then sodium hydrogen carbonate was added tothe residue to adjust pH to 10. The mixture was extracted with ethylacetate and the extract was dried over anhydrous sodium sulfate. Thesolvent was removed and the resulting residue was purified on a silicagel column chromatography (ethyl acetate: methanol=3:1) to obtain4,6-dichloro-2-[4-(pyrrolidine-1-yl)piperidine-1-yl]pyrimidine (787 mg,22%).

MS (EI) m/z:300 (M⁺)

HRMS (EI): Calcd for C₁₃H₁₈Cl₂N₄: 300.0909; found:300.0923

Reference Example 3

To a tetrahydrofuran solution of lithium diisopropylamide (which wasprepared by diluting diisopropylamine (0.7 mL) with tetrahydrofuran (10mL), followed by the addition of n-butyllithium (3.1 mL, 1.6 mol/Lhexane solution) at −20° C. and then stirring at −20° C. for 1 hour), atetrahydrofuran solution of 4,6-dichloro-2-(morpholine-4-yl)pyrimidine(953 mg) (5 mL) was added at −78° C. and the mixture was stirred for 4hours. Carbon dioxide was then bubbled through the reaction mixture for10 min. and water was added. The temperature of the mixture was thenallowed to rise to room temperature. Following the addition of 2 mol/Lhydrochloric acid (8 mL) to adjust pH to 1, the mixture was extractedwith ethyl acetate and the extract was dried over anhydrous sodiumsulfate. The solvent was removed and the residue was washed withdiisopropylether to obtain4,6-dichloro-2-(morpholine-4-yl)pyrimidine-5-carboxylic acid (1.15 g,100%).

MS (EI) m/z:277 (M⁺)

HRMS (EI): Calcd for C₉H₉Cl₂N₃O₃: 277.0021; found:277.0038

Reference Example 4

In a similar manner to Reference Example 3,4,6-dichloro-2-(methylthio)pyrimidine (2.70 g) was used to obtain4,6-dichloro-2-(methylthio)pyrimidine-5-carboxylic acid (1.93 g, 58%).

MS (EI) m/z:238(M⁺)

HRMS (EI): Calcd for C₆H₄Cl₂N₂O₂S:237.9371; found:237.9383

Reference Example 5

4,6-dichloro-2-(morpholine-4-yl)pyrimidine-5-carboxylic acid (Compoundof Reference Example 3; 1.10 g) and N,N-dimethylformamide (3 droplets)were added to thionyl chloride (3.0 mL). While heated, the mixture wasrefluxed for 2 hour. The reaction mixture was then distilled underreduced pressure to obtain a yellow residue.

3-(3,5-bis(trifluoromethyl)benzylamino)propanol (prepared according tothe method described in Japanese Patent Laid-Open Publication No. Hei9-263585; 1.25 g) and triethylamine (1.7 mL) were dissolved intetrahydrofuran (40 mL). While the solution was chilled on an ice bath,a tetrahydrofuran solution of the yellow residue (4 mL) was added. Afterstirred for 1 hour, the mixture was further stirred for additional 3hours at room temperature. The reaction mixture was diluted with ethylacetate, was sequentially washed with water and a saturated aqueoussolution of sodium chloride, and was then dried over anhydrous sodiumsulfate. Following removal of the solvent, the residue was purified on asilica gel column chromatography (ethyl acetate: hexane=1:1) to obtainN-[3,5-bis(trifluoromethyl)benzyl]-4,6-dichloro-2-(morpholine-4-yl)pyrimidine-5-carboxylicacid amide (1.83 g, 82%).

MS (FAB⁺) m/z:561 (M+H⁺)

HRMS (FAB⁺): Calcd for C₂₁H₂₁Cl₂F₆N₄O₃: 561.0895; found:561.0897

Reference Example 6

Following similar procedures to those described in Reference Example 3and then those in Reference Example 5,4,6-dichloro-2-[4-(pyrrolidine-1-yl)piperidine-1-yl]pyrimidine (Compoundof Reference Example 2; 787 mg) was used to obtainN-[3,5-bis(trifluoromethyl)benzyl]-4,6-dichloro-2-[4-(pyrrolidine-1-yl)piperidine-1-yl]pyrimidine-5-carboxylicacid amide (1.30 g, 79%).

MS (FAB⁺) m/z: 628 (M+H⁺)

HRMS (FAB⁺): Calcd for C₂₆H₃₀Cl₂F₆N₅O₂:628.1681; found: 628.1658

Reference Example 7

N-[3,5-bis(trifluoromethyl)benzyl]-4,6-dichloro-2-(morpholine-4-yl)pyrimidine-5-carboxylicacid amide (Compound of Reference Example 5; 1.77 g) was dissolved intetrahydrofuran (30 mL). To this solution, sodium hydride (150 mg, 60%oil suspension) was added and the resulting mixture was refluxed for 3hours while heated. Subsequently, the mixture was allowed to cool andwater was added. The mixture was then diluted with ethyl acetate, waswashed with a saturated aqueous solution of sodium chloride, and wasthen dried over anhydrous sodium sulfate. The solvent was removed andthe resulting residue was purified on a silica gel column chromatography(ethyl acetate:hexane=2:1) to obtain5-[3,5-bis(trifluoromethyl)benzyl]-7-chloro-9-(morpholine-4-yl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(1.17 g, 71%).

MS (EI) m/z:524(M⁺)

HRMS (EI): Calcd for C₂₁H₁₉ClF₆N₄O₃:524.1050; found :524.1030

Reference Example 8

In a similar manner to Reference Example 7,N-[3,5-bis(trifluoromethyl)benzyl]-4,6-dichloro-2-[4-(pyrrolidine-1-yl)piperidine-1-yl]pyrimidine-5-carboxylicacid amide (Compound of Reference Example 6; 1.23 g) was used to obtain5-[3,5-bis(trifluoromethyl)benzyl]-7-chloro-6-oxo-9-[4-(pyrrolidine-1-yl)piperidine-1-yl]-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(180 mg, 16%).

MS (EI) m/z:591(M⁺)

HRMS (EI): Calcd for C₂₆H₂₈ClF₆N₅O₂:591.1836; found:591.1826

Reference Example 9

4,6-dichloro-2-(methylthio)pyrimidine-5-carboxylic acid (Compound ofReference Example 4; 14.0 g) and N,N-dimethylformamide (3 droplets) wereadded to thionyl chloride (40 mL). While heated, the mixture wasrefluxed for 2 hour. The reaction mixture was then distilled underreduced pressure to obtain a yellow residue.

3-(3,5-bis(trifluoromethyl)benzylamino)propanol (18.5 g) andtriethylamine (40 mL) were dissolved in tetrahydrofuran (100 mL). Whilethe solution was chilled on an ice bath, a tetrahydrofuran solution ofthe yellow residue (80 mL) was added. After stirred for 1 hour, themixture was further stirred for additional 2 hours at room temperature.The reaction mixture was then diluted with ethyl acetate, wassequentially washed with water, 1 mol/L hydrochloric acid, and asaturated aqueous solution of sodium chloride, and was then dried overanhydrous sodium sulfate. Following removal of the solvent, theresulting brown residue was dissolved in N,N-dimethylformamide (60 mL).To this solution, potassium carbonate (24.3 g) was added and theresulting mixture was stirred at 80° C. for 1 hour. Subsequently, thereaction mixture was allowed to cool, was diluted with ethyl acetate,was sequentially washed with water and a saturated aqueous solution ofsodium chloride, and was then dried over anhydrous sodium sulfate.Following removal of the solvent, the residue was purified on a silicagel column chromatography (ethyl acetate:hexane=1:1) to obtain5-[3,5-bis(trifluoromethyl)benzyl]-7-chloro-9-(methylthio)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(17.8 g, 63%).

MS (EI) m/z:485 (M⁺)

HRMS (EI): Calcd for C₁₈H₁₄ClF₆N₃O₂S:485.0399; found:485.0358

Reference Example 10

In a similar manner to Reference Example 9,4,6-dichloro-2-(methylthio)pyrimidine-5-carboxylic acid (Compound ofReference Example 4; 5.00 g) was reacted with2-(3,5-bis(trifluoromethyl)benzylamino)ethanol (prepared according tothe method described in Japanese Patent Laid-Open Publication No. Hei9-263585; 6.30 g) to obtain4-[3,5-bis(trifluoromethyl)benzyl]-6-chloro-8-(methylthio)-5-oxo-2,3,4,5-tetrahydropyrimido[5,4-f][1,4]oxazepine(5.15 g, 52%).

MS (EI) m/z: 471 (M⁺)

HRMS (EI): Calcd for C₁₇H₁₂ClF₆N₃O₂S:471.0243; found:471.0236

Reference Example 11

4-fluorophenylboronic acid (387 mg),tetrakis(triphenylphosphine)palladium (133 mg), toluene(10 ml),1,4-dioxane(5 ml), and a 2 mol/L aqueous solution of sodium carbonate(10 ml) were added to5-[3,5-bis(trifluoromethyl)benzyl]-7-chloro-9-(methylthio)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(Compound of Reference Example 9; 1.12 g). While heated, the resultingmixture was refluxed for 6 hours under a stream of argon gas.Subsequently, the reaction mixture was diluted with ethyl acetate, waswashed with a 2 mol/L aqueous solution of sodium carbonate, and was thendried over anhydrous sodium sulfate. The solvent was removed and theresulting residue was purified on a silica gel column chromatography(ethyl acetate: hexane=1:1) to obtain5-[3,5-bis(trifluoromethyl)benzyl]-7-(4-fluorophenyl)-9-(methylthio)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(1.22 g, 97%).

MS (EI) m/z:545(M⁺)

HRMS (EI): Calcd for C₂₄H₁₈F₇N₃O₂S:545.1008; found:545.1017

Reference Example 12

In a similar manner to Reference Example 11,5-[3,5-bis(trifluoromethyl)benzyl]-7-chloro-9-(methylthio)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(Compound of Reference-Example 9; 4.86 g) was reacted with2-methylphenylboronic acid (1.64 g) to obtain5-[3,5-bis(trifluoromethyl)benzyl]-7-(2-methylphenyl)-9-(methylthio)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(5.12 g, 95%).

MS (EI) m/z: 541 (M⁺)

HRMS (EI): Calcd for C₂₅H₂₁F₆N₃O₂S:541.1259; found:541.1241

Reference Example 13

In a similar manner to Reference Example 11,5-[3,5-bis(trifluoromethyl)benzyl]-7-chloro-9-(methylthio)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(Compound of Reference Example 9; 1.95 g) was reacted with2-methoxyphenylboronic acid (730 mg) to obtain5-[3,5-bis(trifluoromethyl)benzyl]-7-(2-methoxyphenyl)-9-(methylthio)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(1.96 g, 88%).

MS (EI) m/z: 557(M⁺)

HRMS (EI): Calcd for C₂₅H₂₁F₆N₃O₃S:557.1208; found:557.1216

Reference Example 14

In a similar manner to Reference Example 11,5-[3,5-bis(trifluoromethyl)benzyl]-7-chloro-9-(methylthio)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(Compound of Reference Example 9; 1.22 g) was reacted with4-fluoro-2-methylphenylboronic acid (464 mg) to obtain5-[3,5-bis(trifluoromethyl)benzyl]-7-(4-fluoro-2-methylphenyl)-9-(methylthio)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(1.35 g, 96%).

MS (EI) m/z:559(M⁺)

HRMS (EI): Calcd for C₂₅H₂₀F₇N₃O₂S:559.1164; found :559.1176

Reference Example 15

In a similar manner to Reference Example 11,5-[3,5-bis(trifluoromethyl)benzyl]-7-chloro-9-(methylthio)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(Compound of Reference Example 9; 2.43 g) was reacted with phenylboronicacid (732 mg) to obtain5-[3,5-bis(trifluoromethyl)benzyl]-7-phenyl-9-(methylthio)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(2.28 g, 86%).

MS (EI) m/z: 527 (M⁺)

HRMS (EI): Calcd for C₂₄H₁₉F₆N₃O₂S:527.1102; found:527.1130

Reference Example 16

In a similar manner to Reference Example 11,4-[3,5-bis(trifluoromethyl)benzyl]-6-chloro-8-(methylthio)-5-oxo-2,3,4,5-tetrahydropyrimido[5,4-f][1,4]oxazepine(Compound of Reference Example 10; 2.36 g) was reacted with2-methylphenylboronic acid (816 mg) to obtain4-[3,5-bis(trifluoromethyl)benzyl]-6-(2-methylphenyl)-8-(methylthio)-5-oxo-2,3,4,5-tetrahydropyrimido[5,4-f][1,4]oxazepine(2.13 g, 81%).

MS (EI) m/z: 527 (M⁺)

HRMS (EI): Calcd for C₂₄H₁₉F₆N₃O₂S:527.1102; found:527.1130

Reference Example 17

5-[3,5-bis(trifluoromethyl)benzyl]-7-(4-fluorophenyl)-9-(methylthio)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(Compound of Reference Example 11; 1.15 g) was dissolved intetrahydrofuran (6 mL). While the solution was chilled on an ice bath,3-chloroperbenzoic acid (1.09 g) was added and the mixture was stirredat room temperature for 3 hours. Subsequently, the reaction mixture wasdiluted with ethyl acetate, was washed with saturated sodium hydrogencarbonate, and was then dried over anhydrous sodium sulfate. The solventwas removed and the resulting residue was purified on a silica gelcolumn chromatography (ethyl acetate:hexane 2:1) to obtain5-[3,5-bis(trifluoromethyl)benzyl]-7-(4-fluorophenyl)-9-(methylsulfonyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(990 mg, 81%).

MS (EI) m/z: 577 (M⁺)

HRMS (EI): Calcd for C₂₄H₁₈F₇N₃O₄S:577.0906; found:577.0898

Reference Example 18

In a similar manner to Reference Example 17,5-[3,5-bis(trifluoromethyl)benzyl]-7-(2-methylphenyl)-9-(methylthio)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(Compound of Reference Example 12; 4.50 g) was used to obtain5-[3,5-bis(trifluoromethyl)benzyl]-7-(2-methylphenyl)-9-(methylsulfonyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(4.98 g, 100%).

MS (EI) m/z: 573 (M⁺)

HRMS (EI): Calcd for C₂₅H₂₁F₆N₃O₄S:573.1157; found:573.1144

Reference Example 19

In a similar manner to Reference Example 17,5-[3,5-bis(trifluoromethyl)benzyl]-7-(2-methoxyphenyl)-9-(methylthio)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(Compound of Reference Example 13; 1.80 g) was used to obtain5-[3,5-bis(trifluoromethyl)benzyl]-7-(2-methoxyphenyl)-9-(methylsulfonyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(1.75 g, 85%).

MS (EI) m/z: 589 (M⁺)

HRMS (EI): Calcd for C₂₅H₂₁F₆N₃O₅S:589.1106; found:589.1082

Reference Example 20

In a similar manner to Reference Example 17,5-[3,5-bis(trifluoromethyl)benzyl]-7-(4-fluoro-2-methylphenyl)-9-(methylthio)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(Compound of Reference Example 14; 1.22 g) was used to obtain5-[3,5-bis(trifluoromethyl)benzyl]-7-(4-fluoro-2-methylphenyl)-9-(methylsulfonyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(1.29 g, 100%).

MS (EI) m/z: 591 (M⁺)

HRMS (EI): Calcd for C₂₅H₂₀F₇N₃O₄S:591.1063; found:591.1063

Reference Example 21

In a similar manner to Reference Example 17,5-[3,5-bis(trifluoromethyl)benzyl]-9-(methylthio)-6-oxo-7-phenyl-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(Compound of Reference Example 15; 2.15 g) was used to obtain5-[3,5-bis(trifluoromethyl)benzyl]-9-(methylsulfonyl)-6-oxo-7-phenyl-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(1.77 g, 78%).

MS (EI) m/z: 559 (M⁺)

HRMS (EI): Calcd for C₂₄H₁₉F₆N₃O₄S:559.1000; found:559.0974

Reference Example 22

In a similar manner to Reference Example 17,4-[3,5-bis(trifluoromethyl)benzyl]-6-(methylphenyl)-8-(methylthio)-5-oxo-2,3,4,5-tetrahydropyrimido[5,4-f][1,4]oxazepine(Compound of Reference Example 16; 1.95 g) was used to obtain4-[3,5-bis(trifluoromethyl)benzyl]-6-(2-methylphenyl)-8-(methylsulfonyl)-5-oxo-2,3,4,5-tetrahydropyrimido[5,4-f][1,4]oxazepine(1.73 g, 84%).

MS (EI) m/z: 559 (M⁺)

HRMS (EI): Calcd for C₂₄H₁₉F₆N₃O₄S:559.1000; found:559.1016

Reference Example 23

3-amino-1-propanol (150 g) was dissolved in tetrahydrofuran (200 mL),followed by the addition of benzylamine(23.8 g). The mixture was stirredat room temperature for 1 hour. Subsequently, the reaction mixture wasdiluted with ethyl acetate, was sequentially washed with water and asaturated aqueous solution of sodium chloride, and was then dried overanhydrous sodium sulfate. The solvent was removed to obtain3-(benzylamino)-1-propanol (20.1 g, 61%).

MS (EI) m/z: 165 (M⁺)

Reference Example 24

In a similar manner to Reference Example 23, 3-amino-1-propanol (27.0 g)was reacted with 2-methoxybenzylchloride (5.00 g) to obtain3-(2-methoxybenzylamino)-1-propanol (3.48 g, 50%).

MS (EI) m/z: 195 (M⁺)

Reference Example 25

In a similar manner to Reference Example 23, 3-amino-1-propanol (52.0 g)was reacted with 4-fluorobenzylchloride (10.0 g) to obtain3-(4-fluorobenzylamino)-1-propanol (8.10 g, 64%).

MS (EI) m/z: 183 (M⁺)

Reference Example 26

In a similar manner to Reference Example 9,4,6-dichloro-2-(methylthio)pyrimidine-5-carboxylic acid (Compound ofReference Example 4; 600 mg) was reacted with 3-(benzylamino)propanol(Compound of Reference Example 23; 500 mg) to obtain5-benzyl-7-chloro-9-(methylthio)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(274 mg, 31%).

MS (EI) m/z: 349 (M⁺)

HRMS (EI): Calcd for C₁₆H₁₆ClN₃O₂S:349.0652; found:349.0636

Reference Example 27

In a similar manner to Reference Example 9,4,6-dichloro-2-(methylthio)pyrimidine-5-carboxylic acid (Compound ofReference Example 4; 600 mg) was reacted with3-(2-methoxybenzylamino)propanol (Compound of Reference Example 24; 589mg) to obtain7-chloro-5-(2-methoxybenzyl)-9-(methylthio)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(213 mg, 22%).

MS (EI) m/z: 379 (M⁺)

HRMS (EI): Calcd for C₁₇H₁₈ClN₃O₃S:379.0757; found:379.0779

Reference Example 28

In a similar manner to Reference Example 9,4,6-dichloro-2-(methylthio)pyrimidine-5-carboxylic acid (Compound ofReference Example 4; 600 mg) was reacted with3-(4-fluorobenzylamino)propanol (Compound of Reference Example 25; 554mg) to obtain7-chloro-5-(4-fluorobenzyl)-9-(methylthio)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(284 mg, 31%).

MS (EI) m/z: 367 (M⁺)

HRMS (EI): Calcd for C₁₆H₁₅ClFN₃O₂S:367.0558; found:367.0541

Reference Example 29

In a similar manner to Reference Example 11,5-benzyl-7-chloro-9-(methylthio)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(Compound of Reference Example 26; 245 mg) was reacted with2-methylphenylboronic acid (115 mg) to obtain5-benzyl-7-(2-methylphenyl)-9-(methylthio)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(230 mg, 81%).

MS (FAB⁺) m/z: 406 (M+H⁺)

HRMS (FAB⁺): Calcd for C₂₃H₂₄N₃O₂S:406.1589; found:406.1599

Reference Example 30

In a similar manner to Reference Example 11,7-chloro-5-(2-methoxybenzyl)-9-(methylthio)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(Compound of Reference Example 27; 197 mg) was reacted with2-methylphenylboronic acid (85.0 mg) to obtain5-(2-methoxybenzyl)-7-(2-methylphenyl)-9-(methylthio)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(212 mg, 94%).

MS (FAB⁺) m/z: 436 (M+H⁺)

HRMS (FAB⁺): Calcd for C₂₄H₂₆N₃O₃S:436.1695; found:436.1694

Reference Example 31

In a similar manner to Reference Example 11,7-chloro-5-(4-fluorobenzyl)-9-(methylthio)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(Compound of Reference Example 28; 231 mg) was reacted with2-methylphenylboronic acid (103 mg) to obtain5-(4-fluorobenzyl)-7-(2-methylphenyl)-9-(methylthio)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(257 mg, 97%).

MS (FAB⁺) m/z: 424 (M+H⁺)

HRMS (FAB⁺): Calcd for C₂₃H₂₃FN₃O₂S:424.1495; found:424.1504

Reference Example 32

In a similar manner to Reference Example 17,5-benzyl-7-(2-methylphenyl)-9-(methylthio)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(Compound of Reference Example 29; 215 mg) was used to obtain5-benzyl-7-(2-methylphenyl)-9-(methylsulfonyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(210 mg, 91%).

MS (FAB⁺) m/z: 438 (M+H⁺)

HRMS (FAB⁺): Calcd for C₂₃H₂₄N₃O₄S:438.1488; found:438.1461

Reference Example 33

In a similar manner to Reference Example 17,5-(2-methoxybenzyl)-7-(2-methylphenyl)-9-(methylthio)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(Compound of Reference Example 30; 202 mg) was used to obtain5-(2-methoxybenzyl)-7-(2-methylphenyl)-9-(methylsulfonyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4.5-b][1,5]oxazocine(188 mg, 87%).

MS (FAB⁺) m/z: 468 (M+H⁺)

HRMS (FAB⁺): Calcd for C₂₄H₂₆N₃O₅S:468.1593; found:468.1583

Reference Example 34

In a similar manner to Reference Example 17,5-(4-fluorobenzyl)-7-(2-methylphenyl)-9-(methylthio)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(Compound of Reference Example 31; 230 mg) was used to obtain5-(4-fluorobenzyl)-7-(2-methylphenyl)-9-(methylsulfonyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(225 mg, 91%).

MS (FAB⁺) m/z: 456 (M+H⁺)

HRMS (FAB⁺): Calcd for C₂₃H₂₃FN₃O₄S:456.1393; found:456.1413

Example 1

Phenylboronic acid (27.4 mg), tetrakis(triphenylphosphine)palladium (8.8mg), toluene (1 ml), 1,4-dioxane (0.5 ml), and a 2 mol/L aqueoussolution of sodium carbonate (1 ml) were added to5-[3,5-bis(trifluoromethyl)benzyl]-7-chloro-9-(morpholine-4-yl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(Compound of Reference Example 7; 78.8 mg). While heated, the mixturewas refluxed for 3 hours under a stream of argon gas. Subsequently, thereaction mixture was diluted with ethyl acetate, was washed with a 2mol/L aqueous solution of sodium carbonate, and was then dried overanhydrous sodium sulfate. The solvent was removed and the resultingresidue was purified on a silica gel column chromatography (ethylacetate:hexane=2:1) to obtain5-[3,5-bis(trifluoromethyl)benzyl]-9-(morpholine-4-yl)-6-oxo-7-phenyl-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(80.9 mg, 95%) in the form of yellow amorphous product.

MS (EI) m/z: 566 (M⁺)

HRMS (EI): Calcd for C₂₇H₂₄F₆N₄O₃: 566.1753; found:566.1760

Example 2

In a similar manner to Example 1,5-[3,5-bis(trifluoromethyl)benzyl]-7-chloro-9-(morpholine-4-yl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b](1,5]oxazocine(Compound of Reference Example 7; 78.8 mg) was reacted with2-fluorophenylboronic acid (31.5 mg) to obtain5-[3,5-bis(trifluoromethyl)benzyl]-7-(2-fluorophenyl)-9-(morpholine-4-yl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(75.6 mg, 86%).

MS (EI) m/z: 584 (M⁺)

HRMS (EI): Calcd for C₂₇H₂₃F₇N₄O₃: 584.1658; found:584.1650

¹H-NMR (400 Mz, CDCl₃) ppm:2.00-2.09(2H, m), 3.29-3.38(1H, m),3.71-3.78(4H, m), 3.81-3.92(5H, m), 3.99(1H, d, J=15.1 Hz),4.32-4.45(2H, m), 5.36(1H, d, J=15.1 Hz), 6.92-6.98(1H, m),7.16-7.22(1H, m), 7.31-7.37(1H, m), 7.44-7.50(1H, m), 7.73(2H, s),7.82(1H, s)

Example 3

In a similar manner to Example 1,5-[3,5-bis(trifluoromethyl)benzyl]-7-chloro-9-(morpholine-4-yl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(Compound of Reference Example 7; 78.8 mg) was reacted with2-methylphenylboronic acid (30.6 mg) to obtain5-[3,5-bis(trifluoromethyl)benzyl]-7-(2-methylphenyl)-9-(morpholine-4-yl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(74.4 mg, 85%).

MS (EI) m/z: 580 (M⁺)

HRMS (EI): Calcd for C₂₈H₂₆F₆N₄O₃: 580.1909; found:580.1948

Example 4

In a similar manner to Example 1,5-[3,5-bis(trifluoromethyl)benzyl]-7-chloro-9-(morpholine-4-yl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(Compound of Reference Example 7; 78.8 mg) was reacted with2-chlorophenylboronic acid (28.1 mg) to obtain5-[3,5-bis(trifluoromethyl)benzyl]-7-(2-chlorophenyl)-9-(morpholine-4-yl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(79.0 mg, 88%).

MS (EI) m/z: 600 (M⁺)

HRMS (EI): Calcd for C₂₇H₂₃ClF₆N₄O₃: 600.1363; found:600.1375

Example 5

In a similar manner to Example 1,5-[3,5-bis(trifluoromethyl)benzyl]-7-chloro-9-(morpholine-4-yl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(Compound of Reference Example 7; 78.8 mg) was reacted with4-fluorophenylboronic acid (25.2 mg) to obtain5-[3,5-bis(trifluoromethyl)benzyl]-7-(4-fluorophenyl)-9-(morpholine-4-yl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(61.5 mg, 70%).

MS (EI) m/z: 584 (M⁺)

HRMS (EI): Calcd for C₂₇H₂₃F₇N₄O₃: 584.1658; found:584.1659

Example 6

In a similar manner to Example 1,5-[3,5-bis(trifluoromethyl)benzyl]-7-chloro-9-(morpholine-4-yl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(Compound of Reference Example 7; 78.8 mg) was reacted with2,4-difluorophenylboronic acid (28.4 mg) to obtain5-[3,5-bis(trifluoromethyl)benzyl]-7-(2,4-difluorophenyl)-9-(morpholine-4-yl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(77.8 mg, 86%).

MS (EI) m/z: 602 (M⁺)

HRMS (EI): Calcd for C₂₇H₂₂F₈N₄O₃: 602.1564; found:602.1589

Example 7

In a similar manner to Example 1,5-[3,5-bis(trifluoromethyl)benzyl]-7-chloro-9-(morpholine-4-yl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(Compound of Reference Example 7; 78.8 mg) was reacted with4-methoxyphenylboronic acid (27.4 mg) to obtain5-[3,5-bis(trifluoromethyl)benzyl]-7-(4-methoxyphenyl)-9-(morpholine-4-yl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(72.0 mg, 80%).

MS (EI) m/z: 596 (M⁺)

HRMS (EI): Calcd for C₂₈H₂₆F₆N₄O₄: 596.1858; found:596.1871

Example 8

In a similar manner to Example 1,5-[3,5-bis(trifluoromethyl)benzyl]-7-chloro-9-(morpholine-4-yl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(Compound of Reference Example 7; 78.8 mg) was reacted with2,4-dimethoxyphenylboronic acid (32.8 mg) to obtain5-[3,5-bis(trifluoromethyl)benzyl]-7-(2,4-dimethoxyphenyl)-9-(morpholine-4-yl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(73.8 mg, 79%).

MS (EI) m/z: 626 (M⁺)

HRMS (EI): Calcd for C₂₉H₂₈F₆N₄O₅: 626.1964; found:626.1951

Example 9

In a similar manner to Example 1,5-[3,5-bis(trifluoromethyl)benzyl]-7-chloro-9-(morpholine-4-yl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(Compound of Reference Example 7; 78.8 mg) was reacted with4-(dimethylamino)phenylboronic acid (29.7 mg) to obtain5-[3,5-bis(trifluoromethyl)benzyl]-7-[4-(dimethylamino)phenyl]-9-(morpholine-4-yl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(56.0 mg, 61%).

MS (EI) m/z: 609 (M⁺)

HRMS (EI): Calcd for C₂₉H₂₉F₆N₅O₃: 609.2175; found:609.2153

Example 10

In a similar manner to Example 1,5-[3,5-bis(trifluoromethyl)benzyl]-7-chloro-9-(morpholine-4-yl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(Compound of Reference Example 7; 78.8 mg) was reacted with2-methoxyphenylboronic acid (27.4 mg) to obtain5-[3,5-bis(trifluoromethyl)benzyl]-7-(2-methoxyphenyl)-9-(morpholine-4-yl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(77.5 mg, 87%).

MS (EI) m/z: 596 (M⁺)

HRMS (EI): Calcd for C₂₈H₂₆F₆N₄O₄: 596.1858; found:596.1843

Example 11

In a similar manner to Example 1,5-[3,5-bis(trifluoromethyl)benzyl]-7-chloro-6-oxo-9-[4-(pyrrolidine-1-yl)piperidine-1-yl]-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(Compound of Reference Example 8; 80.0 mg) was reacted withphenylboronic acid (20.0 mg) to obtain5-[3,5-bis(trifluoromethyl)benzyl]-6-oxo-7-phenyl-9-[4-(pyrrolidine-1-yl)piperidine-1-yl]-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(51.8 mg, 61%).

MS (EI) m/z: 633 (M⁺)

HRMS (EI): Calcd for C₃₂H₃₃F₆N₅O₂: 633.2538; found: 633.2507

Example 12

In a similar manner to Example 1,5-[3,5-bis(trifluoromethyl)benzyl]-7-chloro-6-oxo-9-[4-(pyrrolidine-1-yl)piperidine-1-yl]-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(Compound of Reference Example 8; 80.0 mg) was reacted with2-methylphenylboronic acid (22.0 mg) to obtain5-[3,5-bis(trifluoromethyl)benzyl]-7-(2-methylphenyl)-6-oxo-9-[4-(pyrrolidine-1-yl)piperidine-1-yl]-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(45.0 mg, 51%).

MS (EI) m/z: 647 (M⁺)

HRMS (EI): Calcd for C₃₃H₃₅F₆N₅O₂:647.2695; found:647.2707

Example 13

4-(pyrrolidine-1-yl)piperidine (268 mg), diisopropylethylamine (0.6 mL),and 1,4-dioxane (10 mL) were added to5-[3,5-bis(trifluoromethyl)benzyl]-7-(4-fluorophenyl)-9-(methylsulfonyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(Compound of Reference Example 17; 914 mg). The mixture was refluxed for5 hours while heated. Following removal of the solvent under reducedpressure, the resulting residue was diluted with ethyl acetate, wassequentially washed with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride, and wasthen dried over anhydrous sodium sulfate. The solvent was removed andthe resulting residue was purified on a silica gel column chromatography(ethyl acetate:methanol=5:1) to obtain5-[3,5-bis(trifluoromethyl)benzyl]-7-(4-fluorophenyl)-6-oxo-9-[4-(pyrrolidine-1-yl)piperidine-1-yl]-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(631 mg, 61%).

MS (EI) m/z: 651(M⁺)

HRMS (EI): Calcd for C₃₂H₃₂F₇N₅O₂: 651.2444; found:651.2398

¹H-NMR(400 Mz, CDCl₃) ppm:1.46-1.87(6H, m), 1.92-2.17(4H, m),2.24-2.36(1H, m), 2.56-2.69(4H, m), 2.99(2H, dd, J=13.2and13.2 Hz),3.39-3.48(1H, m), 3.90-3.99(1H, m), 4.05(1H, d, J=15.1 Hz),4.31-4.38(2H, m), 4.67-4.81(2H, m), 5.33(1H, d, J=15.1 Hz),6.90-6.98(2H, m), 7.39-7.45(2H, m), 7.76(2H, s), 7.86(1H, s)

Example 14

In a similar manner to Example 13,5-[3,5-bis(trifluoromethyl)benzyl]-9-(methylsulfonyl)-7-(2-methylphenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(Compound of Reference Example 18; 86.0 mg) was reacted with1-(pyrimidine-2-yl)piperazine dihydrochloride (43.0 mg) to obtain5-(3,5-bis(trifluoromethyl)benzyl]-7-(2-methylphenyl)-6-oxo-9-[4-(pyrimidine-2-yl)piperazine-1-yl]-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(56.2 mg, 57%).

MS (EI) m/z: 657 (M⁺)

HRMS (EI): Calcd for C₃₂H₂₉F₆N₇O₂: 657.2287; found:657.2283

1H-NMR(400 Mz, CDCl₃) ppm:1.93-2.03(1H, m), 2.09-2.21(1H, m), 2.27(3H,s), 3.29(1H, dd, J=15.1and4.4 Hz), 3.79-4.00(10H, m), 4.31-4.44(2H, m),5.33(1H, d, J=15.1 Hz), 6.52(1H, t, J=4.6 Hz), 6.95-7.03(1H, m),7.03-7.09(1H, m), 7.21-7.26(2H, m), 7.57(2H, s), 7.80(1H, s), 8.33(2H,d, J=4.6 Hz)

Example 15

In a similar manner to Example 13,5-[3,5-bis(trifluoromethyl)benzyl]-9-(methylsulfonyl)-7-(2-methylphenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(Compound of Reference Example 18; 86.0 mg) was reacted with1-(pyridine-2-yl)piperazine(30.0 mg) to obtain5-[3,5-bis(trifluoromethyl)benzyl]-7-(2-methylphenyl)-6-oxo-9-[4-(pyridine-2-yl)piperazine-1-yl]-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(77.1 mg, 78%).

MS (EI) m/z: 656 (M⁺)

HRMS (EI): Calcd for C₃₃H₃₀F₆N₆O₂: 656.2334; found:656.2310

Example 16

In a similar manner to Example 13,5-[3,5-bis(trifluoromethyl)benzyl]-9-(methylsulfonyl)-7-(2-methylphenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(Compound of Reference Example 18; 86.0 mg) was reacted with1-acetylpiperazine(23.1 mg) to obtain9-(4-acetylpiperazine-1-yl)-5-[3,5-bis(trifluoromethyl)benzyl]-7-(2-methylphenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(60.7 mg, 65%).

MS (EI) m/z: 621 (M⁺)

HRMS (EI): Calcd for C₃₀H₂₉F₆N₅O₃: 621.2175; found:621.2192

¹H-NMR(400 Mz, CDCl₃) ppm:1.92-2.04(1H, m), 2.10-2.20(1H, m), 2.13(3H,s), 2.25(3H, s), 3.30(1H, dd, J=15.1and4.4 Hz), 3.50(2H, dd, J=4.4and4.4Hz), 3.63-3.70(2H, m), 3.76-3.95(6H, m), 4.30-4.43(2H, m), 5.32(1H, d,J=15.1 Hz), 6.95(1H, brd, J=7.3 Hz), 7.05(1H, brdd, J=7.3and7.3 Hz),7.20-7.25(2H, m), 7.57(2H, s), 7.81(1H, s)

Melting point:160.5-163.5° C.

Element analysis: Calcd for C₃₀H₂₉F₆N₅O₃: C, 57.97; H, 4.70; N, 11.27;found: C, 57.90; H, 4.70; N, 11.33.

Example 17

In a similar manner to Example 13,5-[3,5-bis(trifluoromethyl)benzyl]-9-(methylsulfonyl)-7-(2-methylphenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(Compound of Reference Example 18; 86.0 mg) was reacted with1-formylpiperazine (20.6 mg) to obtain5-[3,5-bis(trifluoromethyl)benzyl]-9-(4-formylpiperazine-1-yl)-7-(2-methylphenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(8.0 mg, 9%).

MS (EI) m/z: 607 (M⁺)

HRMS (EI): Calcd for C₂₉H₂₇F₆N₅O₃: 607.2018; found:607.1995

Example 18

In a similar manner to Example 13,5-[3,5-bis(trifluoromethyl)benzyl]-9-(methylsulfonyl)-7-(2-methylphenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(Compound of Reference Example 18; 86.0 mg) was reacted with sodiumimidazole (16.5 mg) to obtain5-[3,5-bis(trifluoromethyl)benzyl]-9-(imidazole-1-yl)-7-(2-methylphenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(53.8 mg, 64%).

MS (EI) m/z: 561 (M⁺)

HRMS (EI): Calcd for C₂₇H₂₁F₆N₅O₂: 561.1599; found:561.1597

¹H-NMR(400 Mz, CDCl₃) ppm:2.01-2.12(1H, m), 2.21-2.32(4H, m), 3.41(1H,dd, J=15.6and4.9 Hz), 3.74-3.85(1H, m), 3.91(1H, d, J=14.6 Hz),4.45-4.57(2H, m), 5.32(1H, d, J=14.6 Hz), 6.94(1H, d, J=7.8 Hz),7.07(1H, dd, J=7.8and7.8 Hz), 7.14(1H, d, J=1.0 Hz), 7.27-7.33(2H, m),7.59(2H, s), 7.84(1H, s), 7.86(1H, d, J=1.0 Hz), 8.58(1H, s)

Example 19

In a similar manner to Example 13,5-[3,5-bis(trifluoromethyl)benzyl]-9-(methylsulfonyl)-7-(2-methylphenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(Compound of Reference Example 18; 86.0 mg) was reacted with a sodiumsalt of 1,2,4-tetrazole (16.5 mg) to obtain5-[3,5-bis(trifluoromethyl)benzyl]-7-(2-methylphenyl)-6-oxo-9-(1,2,4-tetrazole-1-yl)-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(61.8 mg, 73%).

MS (EI) m/z: 562 (M⁺)

HRMS (EI): Calcd for C₂₆H₂₀F₆N₆O₂:562.1552; found:562.1569

Example 20

In a similar manner to Example 13,5-[3,5-bis(trifluoromethyl)benzyl]-9-(methylsulfonyl)-7-(2-methylphenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(Compound of Reference Example 18; 86.0 mg) was reacted with1,1-dioxothiomorpholine (24.5 mg) to obtain5-[3,5-bis(trifluoromethyl)benzyl]-9-(1,1-dioxothiomorpholine-4-yl)-7-(2-methylphenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(12.5 mg, 13%).

MS (EI) m/z: 628 (M⁺)

HRMS (EI): Calcd for C₂₈H₂₆F₆N₄O₄S: 628.1579; found:628.1523

¹H-NMR(400 Mz, CDCl₃) ppm:1.94-2.05(1H, m), 2.11-2.21(1H, m), 2.23(3H,s), 3.00-3.09(4H, m), 3.29-3.37(1H, m), 3.75-3.83(1H, m), 3.86(1H, d,J=14.6 Hz), 4.33-4.44(6H, m), 5.31(1H, d, J=14.6 Hz), 6.93(1H, d, J=6.8Hz), 7.06(1H, dd, J=6.8and6.8 Hz), 7.21-7.30(2H, m), 7.57(2H, s),7.81(1H, s)

Example 21

In a similar manner to Example 13,5-[3,5-bis(trifluoromethyl)benzyl]-9-(methylsulfonyl)-7-(2-methylphenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(Compound of Reference Example 18; 86.0 mg) was reacted with3-(ethoxycarbonyl)piperidine (28.3 mg) to obtain5-[3,5-bis(trifluoromethyl)benzyl]-9-[3-(ethoxycarbonyl)piperidine-1-yl]-7-(2-methylphenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(61.8 mg, 63%).

MS (EI) m/z: 650 (M⁺)

HRMS (EI): Calcd for C₃₂H₃₂F₆N₄O₄: 650.2328; found:650.2351

Example 22

In a similar manner to Example 13,5-[3,5-bis(trifluoromethyl)benzyl]-9-(methylsulfonyl)-7-(2-methylphenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(Compound of Reference Example 18; 86.0 mg) was reacted with4-(ethoxycarbonyl)piperidine (28.3 mg) to obtain5-[3,5-bis(trifluoromethyl)benzyl]-9-[4-(ethoxycarbonyl)piperidine-1-yl]-7-(2-methylphenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(64.6 mg, 68%).

MS (EI) m/z: 650 (M⁺)

HRMS (EI): Calcd for C₃₂H₃₂F₆N₄O₄: 650.2328; found:650.2351

Example 23

In a similar manner to Example 13,5-[3,5-bis(trifluoromethyl)benzyl]-9-(methylsulfonyl)-7-(2-methylphenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(Compound of Reference Example 18; 86.0 mg) was reacted with3-carbamoylpiperidine (23.1 mg) to obtain5-[3,5-bis(trifluoromethyl)benzyl]-9-(3-carbamoylpiperidine-1-yl)-7-(2-methylphenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(74.0 mg, 79%).

MS (EI) m/z: 621 (M⁺)

HRMS (EI): Calcd for C₃₀H₂₉F₆N₅O₃: 621.2175; found:621.2139

Example 24

In a similar manner to Example 13,5-[3,5-bis(trifluoromethyl)benzyl]-9-(methylsulfonyl)-7-(2-methylphenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(Compound of Reference Example 18; 86.0 mg) was reacted with4-carbamoylpiperidine (23.1 mg) to obtain5-[3,5-bis(trifluoromethyl)benzyl]-9-(4-carbamoylpiperidine-1-yl)-7-(2-methylphenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(70.0 mg, 75%).

MS (EI) m/z: 621 (M⁺)

HRMS (EI): Calcd for C₃₀H₂₉F₆N₅O₃: 621.2175; found:621.2142

Example 25

In a similar manner to Example 13,5-[3,5-bis(trifluoromethyl)benzyl]-9-(methylsulfonyl)-7-(2-methylphenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(Compound of Reference Example 18; 86.0 mg) was reacted with3-(dimethylamino)pyrrolidine (20.6 mg) to obtain5-[3,5-bis(trifluoromethyl)benzyl]-9-[3-(dimethylamino)pyrrolidine-1-yl]-7-(2-methylphenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(54.7 mg, 60%).

MS (EI) m/z: 607 (M⁺)

HRMS (EI): Calcd for C₃₀H₃₁F₆N₅O₂: 607.2382; found:607.2368

Example 26

In a similar manner to Example 13,5-[3,5-bis(trifluoromethyl)benzyl]-9-(methylsulfonyl)-7-(2-methylphenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(Compound of Reference Example 18; 86.0 mg) was reacted with1-methylhomopiperazine (20.6 mg) to obtain5-[3,5-bis(trifluoromethyl)benzyl]-9-(4-methylhomopiperazine-1-yl)-7-(2-methylphenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(55.5 mg, 61%).

MS (EI) m/z: 607 (M⁺)

HRMS (EI): Calcd for C₃₀H₃₁F₆N₅O₂: 607.2382; found:607.2362

Example 27

In a similar manner to Example 13,5-[3,5-bis(trifluoromethyl)benzyl]-9-(methylsulfonyl)-7-(2-methylphenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(Compound of Reference Example 18; 86.0 mg) was reacted with3-(acetylamino)pyrrolidine (23.1 mg) to obtain5-[3,5-bis(trifluoromethyl)benzyl]-9-[3-(acetylamino)pyrrolidine-1-yl]-7-(2-methylphenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(65.0 mg, 70%).

MS (EI) m/z: 621 (M⁺)

HRMS (EI): Calcd for C₃₀H₂₉F₆N₅O₃: 621.2175; found:621.2173

¹H-NMR(400 Mz, CDCl₃) ppm:1.90-2.03(5H, m), 2.07-2.19(1H, m),2.19-2.32(4H, m), 3.28(1H, dd, J=15.1and4.9 Hz), 3.49(1H, dd,J=11.7and4.4 Hz), 3.69(2H, dd, J=6.8and6.8 Hz), 3.74-3.91(3H, m),4.29-4.42(2H, m), 4.52-4.62(1H, m), 5.32(1H, d, J=14.6 Hz), 5.63(1H,brs), 6.91-6.98(1H, m), 7.01-7.08(1H, m), 7.18-7.26(2H, m), 7.57(2H, s),7.80(1H, s)

Example 28

In a similar manner to Example 13,5-[3,5-bis(trifluoromethyl)benzyl]-7-(4-fluorophenyl)-9-(methylsulfonyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(Compound of Reference Example 17; 86.6 mg) was reacted with1-acetylpiperazine (48.1 mg) to obtain9-(4-acetylpiperazine-1-yl)-5-[3,5-bis(trifluoromethyl)benzyl]-7-(4-fluorophenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(68.2 mg, 73%).

MS (EI) m/z: 625 (M⁺)

HRMS (EI): Calcd for C₂₉H₂₆F₇N₅O₃: 625.1924; found:625.1972

Example 29

In a similar manner to Example 13,5-[3,5-bis(trifluoromethyl)benzyl]-9-(methylsulfonyl)-7-(2-methoxyphenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(Compound of -Reference Example 19 ;88.5 mg) was reacted with1-acetylpiperazine (48.1 mg) to obtain9-(4-acetylpiperazine-1-yl)-5-[3,5-bis(trifluoromethyl)benzyl]-7-(2-methoxyphenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(86.2 mg, 90%).

MS (EI) m/z: 637 (M⁺)

HRMS (EI): Calcd for C₃₀H₂₉F₆N₅O₄: 637. 2124; found: 637.2085

Example 30

In a similar manner to Example 13,5-[3,5-bis(trifluoromethyl)benzyl]-9-(methylsulfonyl)-6-oxo-7-phenyl-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(Compound of Reference Example 21; 84.0 mg) was reacted with1-acetylpiperazine (23.1 mg) to obtain9-(4-acetylpiperazine-1-yl)-5-[3,5-bis(trifluoromethyl)benzyl]-6-oxo-7-phenyl-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(53.7 mg, 59%).

MS (EI) m/z: 607 (M⁺)

HRMS (EI): Calcd for C₂₉H₂₇F₆N₅O₃: 607.2018; found:607.2049

Example 31

In a similar manner to Example 13,5-[3,5-bis(trifluoromethyl)benzyl]-7-(4-fluoro-2-methylphenyl)-9-(methylsulfonyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(Compound of Reference Example 20; 88.8 mg) was reacted with1-acetylpiperazine (23.1 mg) to obtain9-(4-acetylpiperazine-1-yl)-5-[3,5-bis(trifluoromethyl)benzyl]-7-(4-fluoro-2-methylphenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(47.4 mg, 49%).

MS (EI) m/z: 639 (M⁺)

HRMS (EI): Calcd for C₃₀H₂₈F₇N₅O₃: 639.2080; found:639.2078

Example 32

In a similar manner to Example 13,4-[3,5-bis(trifluoromethyl)benzyl]-6-(2-methylphenyl)-8-(methylsulfonyl)-5-oxo-2,3,4,5-tetrahydropyrimido[5,4-f][1,4]oxazepine(Compound of Reference Example 22; 84.0 mg) was reacted with1-acetylpiperazine (23.1 mg) to obtain8-(4-acetylpiperazine-1-yl)-4-[3,5-bis(trifluoromethyl)benzyl]-6-(2-methylphenyl)-5-oxo-2,3,4,5-tetrahydropyrimido[5,4-f][1,4]oxazepine(62.2 mg, 68%).

MS (EI) m/z: 607 (M⁺)

HRMS (EI): Calcd for C₂₉H₂₇F₆N₅O₃: 607.2018; found:607.2026

Example 33

In a similar manner to Example 13,5-[3,5-bis(trifluoromethyl)benzyl]-7-(2-methylphenyl)-9-(methylsulfonyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(Compound of Reference Example 18; 86.1 mg) was reacted with4-(2-oxopyrrolidine-1-yl)piperidine (30.3 mg) to obtain5-[3,5-bis(trifluoromethyl)benzyl]-7-(2-methylphenyl)-6-oxo-9-[4-(2-oxopyrrolidine-1-yl)piperidine-1-yl]-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(80.8 mg, 81%).

MS (EI) m/z: 661 (M⁺)

HRMS (EI): Calcd for C₃₃H₃₃F₆N₅O₃: 661.2488; found:661.2512

Example 34

In a similar manner to Example 13,5-[3,5-bis(trifluoromethyl)benzyl]-7-(2-methylphenyl)-9-(methylsulfonyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(Compound of Reference Example 18; 86.1 mg) was reacted with4-(morpholine-4-yl)piperidine (30.6 mg) to obtain5-[3,5-bis(trifluoromethyl)benzyl]-7-(2-methylphenyl)-9-[4-(morpholine-4-yl)piperidine-1-yl]-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(72.6 mg, 73%).

MS (EI) m/z: 663 (M⁺)

HRMS (EI): Calcd for C₃₃H₃₅F₆N₅O₃: 663.2644; found:663.2654

Example 35

In a similar manner to Example 13,5-[3,5-bis(trifluoromethyl)benzyl]-7-(2-methylphenyl)-9-(methylsulfonyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(Compound of Reference Example 18; 86.1 mg) was reacted with4-(dimethylamino)piperidine (23.1 mg) to obtain5-[3,5-bis(trifluoromethyl)benzyl]-9-[4-(dimethylamino)piperidine-1-yl]-7-(2-methylphenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(84.2 mg, 90%).

MS (EI) m/z: 621 (M⁺)

HRMS (EI): Calcd for C₃₁H₃₃F₆N₅O₂: 621.2538; found:621.2524

Example 36

In a similar manner to Example 13,5-[3,5-bis(trifluoromethyl)benzyl]-7-(2-methylphenyl)-9-(methylsulfonyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(Compound of Reference Example 18; 86.1 mg) was reacted with4-(piperidine-1-yl)piperidine (30.3 mg) to obtain5-[3,5-bis(trifluoromethyl)benzyl]-7-(2-methylphenyl)-6-oxo-9-[4-(piperidine-1-yl)piperidine-1-yl]-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(86.7 mg, 87%).

MS (EI) m/z: 661 (M⁺)

HRMS (EI): Calcd for C₃₄H₃₇F₆N₅O₂: 661.2851; found:661.2845

Example 37

A mixture of5-[3,5-bis(trifluoromethyl)benzyl]-9-(methylsulfonyl)-7-(2-methylphenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(Compound of Reference Example 18; 86.0 mg),4-(t-butoxycarbonylamino)piperidine (36.1 mg), and 1,4-dioxane(1 mL) wasrefluxed for 5 hours while heated. The reaction mixture was diluted withethyl acetate, was washed with water, and was dried over anhydroussodium sulfate. The solvent was then removed to obtain a residue. Whilethis residue was chilled on an ice bath, 3 mol/L hydrogen chloride-ethylacetate (1 mL) was added and the mixture was stirred for 30 min. andthen another hour at room temperature. The solvent was removed and theremaining product was dissolved in tetrahydrofuran (1 mL). While thesolution was chilled on an ice bath, triethylamine (0.1 mL) and aceticanhydride (0.05 mL) were added and the resulting mixture was stirred atroom temperature for 30 min. The reaction mixture was then diluted withethyl acetate, was washed with water, and was then dried over anhydroussodium sulfate. The solvent was removed and the resulting residue waspurified on a silica gel column chromatography (ethyl acetate) to obtain9-[4-(acetylamino)piperidine-1-yl]-5-[3,5-bis(trifluoromethyl)benzyl]-7-(2-methylphenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(51.0 mg, 53%).

MS (EI) m/z: 635 (M⁺)

HRMS (EI): Calcd for C₃₁H₃₁F₆N₅O₃: 635.2331; found:635.2360

¹H-NMR(400 Mz, CDCl₃) ppm:1.25-1.41(2H, m), 1.91-2.05(6H, m),2.07-2.19(1H, m), 2.25(3H, s), 3.04(2H, dd, J=11.2and11.2 Hz), 3.28(1H,dd, J=14.6and4.9 Hz), 3.75-3.90(1H, m), 3.85(1H, d, J=14.6 Hz),3.99-4.09(1H, m), 4.28-4.42(2H, m), 4.72(2H, brd, J=12.7 Hz),5.28-5.36(1H, m), 5.32(1H, d, J=14.6 Hz), 6.91-6.98(1H, m),7.02-7.08(1H, m), 7.19-7.26(2H, m), 7.57(2H, s), 7.80(1H, s)

Example 38

In a similar manner to Example 37,5-[3,5-bis(trifluoromethyl)benzyl]-9-(methylsulfonyl)-7-(2-methylphenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(Compound of Reference Example 18; 86.0 mg),4-(t-butoxycarbonylamino)piperidine (36.1 mg), andmethylsulfonylchloride (0.05 mL) were reacted to obtain5-[3,5-bis(trifluoromethyl)benzyl]-9-[4-(methylsulfonylamino)piperidine-1-yl]-7-(2-methylphenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(31.7 mg, 31%).

MS (EI) m/z: 671 (M⁺)

HRMS (EI): Calcd for C₃₀H₃₁F₆N₅O₄S:671.2001; found:671.2004

¹H-NMR(400 Mz, CDCl₃) ppm:1.42-1.54(2H, m), 1.91-2.19(5H, m), 2.25(3H,s), 3.00(3H, s), 3.03-3.14(2H, m), 3.25-3.33(1H, m), 3.53-3.65(1H, m),3.75-3.88(1H, m), 3.85(1H, d, J=14.6 Hz), 4.29-4.42(2H, m),4.64-4.75(2H, m), 5.32(1H, d, J=14.6 Hz), 6.92-6.98(1H, m),7.02-7.08(1H, m), 7.19-7.25(2H, m), 7.57(2H, s), 7.80(1H, s)

Example 39

In a similar manner to Example 37,5-[3,5-bis(trifluoromethyl)benzyl]-9-(methylsulfonyl)-7-(2-methylphenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(Compound of Reference Example 18; 86.0 mg),1-(t-butoxycarbonyl)piperazine (33.6 mg), and methylsulfonylchloride(0.05 mL) were reacted to obtain5-[3,5-bis(trifluoromethyl)benzyl]-9-[4-(methylsulfonyl)piperazine-1-yl]-7-(2-methylphenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(54.6 mg, 55%).

MS (EI) m/z: 657 (M⁺)

HRMS (EI): Calcd for C₂₉H₂₉F₆N₅O₄S:657.1844; found:657.1843

Example 40

In a similar manner to Example 37,5-[3,5-bis(trifluoromethyl)benzyl]-9-(methylsulfonyl)-7-(2-methylphenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(Compound of Reference Example 18; 86.0 mg),1-(t-butoxycarbonyl)homopiperazine (36.1 mg), and methylsulfonylchloride(0.05 mL) were reacted to obtain5-[3,5-bis(trifluoromethyl)benzyl]-9-[4-(methylsulfonyl)homopiperazine-1-yl]-7-(2-methylphenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(46.4 mg, 46%).

MS (EI) m/z: 671 (M⁺)

HRMS (EI): Calcd for C₃₀H₃₁F₆N₅O₄S:671.2001; found:671.2030

Example 41

In a similar manner to Example 37,5-[3,5-bis(trifluoromethyl)benzyl]-9-(methylsulfonyl)-7-(2-methylphenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(Compound of Reference Example 18; 86.0 mg),1-(t-butoxycarbonyl)homopiperazine (36.1 mg), and acetic anhydride (0.05mL) were reacted to obtain9-(4-acetylhomopiperazine-1-yl)-5-[3,5-bis(trifluoromethyl)benzyl]-7-(2-methylphenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(39.5 mg, 41%).

MS (EI) m/z: 635 (M⁺)

HRMS (EI): Calcd for C₃₁H₃₁F₆N₅O₃: 635.2331; found:635.2313

¹H-NMR(400 Mz, CDCl₃) ppm:1.83-2.06(4H, m), 2.12(3H, s), 2.25(3H, d,J=3.9 Hz), 3.29(1H, dd, J=15.1and4.4 Hz), 3.33-4.15(10H, m),4.29-4.42(2H, m), 5.31(1H, d, J=15.1 Hz), 6.91-6.98(1H, m),7.01-7.08(1H, m), 7.19-7.25(2H, m), 7.57(2H, s), 7.80(1H, s)

Example 42

In a similar manner to Example 37,5-[3,5-bis(trifluoromethyl)benzyl]-9-(methylsulfonyl)-7-(2-methylphenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(Compound of Reference Example 18; 86.0 mg),3-(t-butoxycarbonylamino)-3-methylpyrrolidine (36.1 mg), and aceticanhydride (0.05 mL) were reacted to obtain9-[3-(acetylamino)-3-methylpyrrolidine-1-yl]-5-[3,5-bis(trifluoromethyl)benzyl]-7-(2-methylphenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(52.9 mg, 56%).

MS (EI) m/z: 635 (M⁺)

HRMS (EI): Calcd for C₃₁H₃₁F₆N₅O₃: 635.2331; found:635.2293

Example 43

A mixture of5-[3,5-bis(trifluoromethyl)benzyl]-9-(methylsulfonyl)-7-(2-methoxyphenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(Compound of Reference Example 19; 118 mg), thiomorpholine (100 mg), and1,4-dioxane (1 mL) was refluxed for 5 hours while heated. The reactionmixture was diluted with ethyl acetate, was washed with water, and wasthen dried over anhydrous sodium sulfate. The solvent was removed andthe resulting residue was purified on a silica gel column chromatography(hexane:ethyl acetate=10:1). The resultant crystal was dissolved intetrahydrofuran (1 mL), followed by addition of 3-chloroperbenzoic acid(105 mg) and stirring for 3 hours at room temperature. Subsequently, thereaction mixture was diluted with ethyl acetate, was washed with asaturated aqueous solution of sodium hydrogen carbonate, and was thendried over anhydrous sodium sulfate. The solvent was removed and theresulting residue was purified on a silica gel column chromatography(hexane:ethyl acetate=2:1) to obtain5-[3,5-bis(trifluoromethyl)benzyl]-9-(1,1-dioxothiomorpholine-4-yl)-7-(2-methoxyphenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(104 mg, 81%).

MS (EI) m/z: 644 (M⁺)

HRMS (EI): Calcd for C₂₈H₂₆F₆N₄O₅S:644.1528; found:644.1555

Example 44

In a similar manner to Example 13,5-[3,5-bis(trifluoromethyl)benzyl]-7-(2-methylphenyl)-9-(methylsulfonyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(Compound of Reference Example 18; 115 mg) was reacted with1-methylpiperazine (40.3 mg) to obtain5-[3,5-bis(trifluoromethyl)benzyl]-7-(2-methylphenyl)-9-(4-methylpiperazine-1-yl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(76.2 mg, 61%).

MS (FAB⁺) m/z: 594 (M+H⁺)

HRMS (FAB⁺): Calcd for C₂₉H₃₀F₆N₅O₂: 594.2304; found:594.2289

Example 45

In a similar manner to Example 13,5-benzyl-7-(2-methylphenyl)-9-(methylsulfonyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(Compound of Reference Example 32; 65.7 mg) was reacted with1-acetylpiperazine (23.1 mg) to obtain9-(4-acetylpiperazine-1-yl)-5-benzyl-7-(2-methylphenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(45.0 mg, 62%).

MS (FAB⁺) m/z: 486 (M+H⁺)

HRMS (FAB⁺): Calcd for C₂₈H₃₂N₅O₃: 486.2505; found:486.2505

Example 46

In a similar manner to Example 13,5-(2-methoxybenzyl)-7-(2-methylphenyl)-9-(methylsulfonyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(Compound of Reference Example 33; 70.2 mg) was reacted with1-acetylpiperazine (23.1 mg) to obtain9-(4-acetylpiperazine-1-yl)-5-(2-methoxybenzyl)-7-(2-methylphenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(48.3 mg, 62%).

MS (FAB⁺) m/z: 516 (M+H⁺)

HRMS (FAB⁺): Calcd for C₂₉H₃₄N₅O₄: 516.2611; found:516.2610

Example 47

In a similar manner to Example 13,5-(4-fluorobenzyl)-7-(2-methylphenyl)-9-(methylsulfonyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(Compound of Reference Example 34; 68.4 mg) was reacted with1-acetylpiperazine (23.1 mg) to obtain9-(4-acetylpiperazine-1-yl)-5-(4-fluorobenzyl)-7-(2-methylphenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine(42.0 mg, 55%).

MS (FAB⁺) m/z: 504 (M+H⁺)

HRMS (FAB⁺): Calcd for C₂₈H₃₁FN₅O₃: 504.2411; found:504.2408

Evidence of the effectiveness of the compounds of the present inventionis provided below with reference to Test Examples.

Test Examples

(1) Test for NK1 Receptor Antagonist

The method used was according to the method proposed by S. Dion etal.(Dion et al., Life Sciences 41(1987): 2269), to which minormodifications were made.

Guinea pigs were stunned by a blow on the head and were exsanguinatedfrom the carotid artery and ilea were isolated. The ileum was mounted inan organ bath containing Tyrode's solution which was maintained at 32°C, and gased with 95% O₂ and 5% CO₂. The ileum was subjected to aresting tension of 1-gram and allowed to equilibrate for 20 minutesbefore the experiment was started. As a control, aconcentration-response curve for substance P in the absence of any oftest compounds was used. The NK1 receptor antagonist activity of eachtest compound was determined by a concentration-response curve obtainedby pretreating at least three concentrations of the test compound for 10minutes and subsequently applying substance P in a cumulative manner.The Kb values were determined according to the method of Schild and theresults are shown in Table 1 (Schild Brit. J. Pharmacol. 14(1959): 49).

The composition of the Tyrode's solution was as follows:

NaCl=136.9, KCl=2.7, CaCl₂.2H₂O=2.5, MgCl₂.6H₂O=1.0, NaH₂PO₄.2H₂O=0.4,NaHCO₃=11.9, glucose=11.1(mmol/L) TABLE 1 Test Compounds Kb(nmol/L)Compound of Example 2  0.294 Compound of Example 13 0.217 Compound ofExample 14 0.798 Compound of Example 16 0.105 Compound of Example 180.459 Compound of Example 20 0.0794 Compound of Example 25 0.427Compound of Example 26 0.398 Compound of Example 27 0.440 Compound ofExample 29 0.100 Compound of Example 37 0.151 Compound of Example 380.214 Compound of Example 41 0.308 Compound of Example 43 0.123 Compoundof Example 44 0.00631 TAK-637* 0.269*Compound described in Example 18 in Japanese Patent Laid-OpenPublication No. Hei 9-263585

As can be seen from the results of Table 1, the compounds (1) or saltsthereof prove to be effective NK1 receptor antagonists.

(2) Cystometry Test on Guinea Pigs

The method used was according to the method proposed by J S. Peterson etal. (Peterson J S. et al., J. Pharmacol. Methods 21(1989): 231), towhich minor modifications were made.

Guinea pigs were anesthetized with halothane and the tenth thoracicspinal cord was cut in each animal. Subsequently, both ureters wereligated and were cut on the kidney-side. Polyethylene catheters wereinserted into the bladder to provide an injection pathway forphysiological saline and a pathway for the measurement of intravesicalpressure. Each animal was restricted in a Ballman cage and was left formore than 2 hours. Subsequently, room-temperature saline was injectedthrough the bladder catheter into the bladder at a rate of 6 mL/hr toconduct a cystometry test. Once the effective bladder capacity wasstabilized, a test compound was intravenously administered into thejugular vein. The effective bladder capacity is defined as the volume ofsaline injected from one urination to the next. The effect of each testcompound was determined as the increase in the average bladder volume,which was determined based on the average bladder volume measured 30minutes prior to the administration of the test compound and the averagebladder volume measured every 30 minutes after the administration of thetest compound. The results are shown in Table 2. TABLE 2 Dose Increasein (i.v.) bladder Test compounds mg/kg capacity (%) Compound of Example16 0.3 59.4 Compound of Example 20 0.3 40.4 Compound of Example 41 0.336.8 TAK-637* 0.3 12.0 1 23.8 3 20.5*Compound described in Example 18 in Japanese Patent Laid-OpenPublication No. Hei 9-263585

As can be inferred from the results of Table 2, the compounds (1) orsalts thereof have a better ability to increase the effective bladdercapacity than TAK-637 in terms of the potency as well as the maximumeffects.

Industrial Applicability

As set forth, the present invention has been devised based on thediscovery that the novel fused bicyclic pyrimidine derivatives and saltsthereof act as effective tachykinin receptor antagonists.

In particular, not only have the compounds of the present inventionproven to act as NK1 receptor antagonists, but they have also beenshown, by the Test Examples above, to have better effects than theconventional compounds.

Specifically, the compounds of the present invention proved to exhibitsignificantly higher pharmacological effects as compared to TAK-637, aknown compound, when tested for their effects on dysuria, atachykinin-mediated disorder, by cystometry, during which the ability ofeach of the compounds to increase the effective bladder capacity wasdetermined in guinea pigs with broken spinal cords. In brief, when givenin smaller doses, the compounds of the present invention exhibitedpharmacological effects comparable to the conventional TAK-637 compound.Also, the same doses of the compounds of the present invention broughtabout significantly better pharmacological effects and elicited highermaximum effects than TAK-637.

In addition, the compounds of the present invention and salts thereofexhibit little toxicity and are thus proven to be highly safe.Accordingly, the compounds of the present invention and salts thereof,which are effective tachykinin antagonists, are of significantusefulness in the treatment of various pathological conditions includingpollakiuria.

1. A fused bicyclic pyrimidine derivative represented by the followinggeneral formula (1), or a salt thereof:

wherein the rings A and B are each a benzene ring, which may have 1 to 3substituents (any adjacent two of which may be bound to one another toform a ring) that are each independently selected from the groupconsisting of a halogen atom, a C₁ to C₆ alkyl group, which may besubstituted with a halogen atom, and a C₁ to C₆ alkoxyl group; the ringC is a 5- to 7-membered nitrogen-containing ring, which may contain,aside from the nitrogen atom, 1 to 3 heteroatoms selected from the groupconsisting of a nitrogen atom, a sulfur atom, and an oxygen atom; thering C may further contain a substituent selected from the groupconsisting of a C₁ to C₆ alkyl group, a hydroxyl group, a C₁ to C₆alkoxyl group, a formyl group, a C₁ to C₆ alkylcarbonyl group, a C₁ toC₆ alkoxycarbonyl group, a carbamoyl group, a mono- or di-substituted C₁to C₆ alkylcarbamoyl group, a C₁ to C₆ alkylsulfonyl group, an aminogroup, a mono- or di-substituted C₁ to C₆ alkylamino group, a C₁ to C₆alkylcarbonylamino group, a C₁ to C₆ alkoxycarbonylamino group, a C₁ toC₆ alkylsulfonylamino group, an oxo group, a 6-membered aromaticheterocyclic group, and a substituent represented by the followingformula:

wherein the ring D is a 3- to 7-membered nonaromatic heterocyclic ring,which may contain, aside from the nitrogen atom, 1 to 3 heteroatomsselected from the group consisting of a nitrogen atom, a sulfur atom,and an oxygen atom and may further contain 1 or 2 oxo-substituted carbonatoms; m is 1 or 2; and n is 2 or
 3. 2. The fused bicyclic pyrimidinederivative according to claim 1 represented by the following generalformula (1a), or a salt thereof:

wherein the ring A is a benzene ring, which may have 1 to 3 substituents(any adjacent two of which may be bound to one another to form a ring)that are each independently selected from the group consisting of ahalogen atom, a C₁ to C₆ alkyl group, which may be substituted with ahalogen atom, and a C₁ to C₆ alkoxyl group; the ring C is a 5- to7-membered nitrogen-containing ring, which may contain, aside from thenitrogen atom, 1 to 3 heteroatoms selected from the group consisting ofa nitrogen atom, a sulfur atom, and an oxygen atom; the ring C mayfurther contain a substituent selected from the group consisting of a C₁to C₆ alkyl group, a hydroxyl group, a C₁ to C₆ alkoxyl group, a formylgroup, a C₁ to C₆ alkylcarbonyl group, a C₁ to C₆ alkoxycarbonyl group,a carbamoyl group, a mono- or di-substituted C₁ to C₆ alkylcarbamoylgroup, a C₁ to C₆ alkylsulfonyl group, an amino group, a mono- ordi-substituted C₁ to C₆ alkylamino group, a C₁ to C₆ alkylcarbonylaminogroup, a C₁ to C₆ alkoxycarbonylamino group, a C₁ to C₆alkylsulfonylamino group, an oxo group, a 6-membered aromaticheterocyclic group, and a substituent represented by the followingformula:

wherein the ring D is a 3- to 7-membered nonaromatic heterocyclic ring,which may contain, aside from the nitrogen atom, 1 to 3 heteroatomsselected from the group consisting of a nitrogen atom, a sulfur atom,and an oxygen atom and may further contain 1 or 2 oxo-substituted carbonatoms; and n is 2 or
 3. 3. The fused bicyclic pyrimidine derivativeaccording to claim 2, or a salt thereof, wherein in the general formula(1a), the ring C is represented either by the following formula:

wherein R¹ is a hydroxyl group, a C1 to C6 alkoxy group, a formyl group,a C1 to C6 alkylcarbonyl group, a C1 to C6 alkoxycarbonyl group, acarbamoyl group, a mono- or di-substituted C1 to C6 alkylcarbamoylgroup, an amino group, a mono- or di-substituted C1 to C6 alkylaminogroup, a C1 to C6 alkylcarbonylamino group, a C1 to C6alkoxycarbonylamino group, a C1 to C6 alkylsulfonylamino group, an oxogroup, a 6-membered aromatic heterocyclic group, or a substituentrepresented by the following formula:

wherein the ring D is a 3- to 7-membered nonaromatic heterocyclic ring,which may contain, aside from the nitrogen atom, 1 to 3 heteroatomsselected from the group consisting of a nitrogen atom, a sulfur atom,and an oxygen atom and may further contain 1 or 2 oxo-substituted carbonatoms.
 4. The fused bicyclic pyrimidine derivative according to claim 2,or a salt thereof, wherein in the general formula (1a), the ring C isrepresented by the following formula:

wherein X is —O— or —S(O)_(q)—; and q is 0, 1, or
 2. 5. The fusedbicyclic pyrimidine derivative according to claim 2, or a salt thereof,wherein in the general formula (1a), the ring C is a functional grouprepresented by the following formula:

wherein R² is a hydrogen atom, a C₁ to C₆ alkyl group, a formyl group, aC₁ to C₆ alkylcarbonyl group, a C₁ to C₆ alkoxycarbonyl group, acarbamoyl group, a mono- or di-substituted C₁ to C₆ alkylcarbamoyl groupor a C₁ to C₆ alkylsulfonyl group; and r is 1 or
 2. 6. The fusedbicyclic pyrimidine derivative according to claim 2, or a salt thereof,wherein in the general formula (1a), the ring C is represented by thefollowing formula:

wherein R^(2′) is an acetyl group or a methylsulfonyl group; and r is 1or
 2. 7. The fused bicyclic pyrimidine derivative according to claim 2,or a salt thereof, wherein the ring C in the general formula (1a) isrepresented by the following formula:


8. The fused bicyclic pyrimidine derivative according to claim 7, or asalt thereof, wherein in the general formula (1a) above, n is
 3. 9. Thecompound according to claim 1, wherein the compound represented by thegeneral formula (1) is9-(4-acetylpiperazine-1-yl)-5-[3,5-bis(trifluoromethyl)benzyl]-7-(2-methylphenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine.10. The compound according to claim 1, wherein the compound representedby the general formula (1) is5-[3,5-bis(trifluoromethyl)benzyl]-9-(1,1-dioxothiomorpholine-4-yl)-7-(2-methylphenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine.11. The compound according to claim 1, wherein the compound representedby the general formula (1) is9-(4-acetylhomopiperazine-1-yl)-5-[3,5-bis(trifluoromethyl)benzyl]-7-(2-methylphenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine.12. The compound according to claim 1, wherein the compound representedby the general formula (1) is5-[3,5-bis(trifluoromethyl)benzyl]-7-(2-methylphenyl)-9-(4-methylpiperazine-1-yl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrimido[4,5-b][1,5]oxazocine.13. A tachykinin receptor antagonist containing as an active ingredientthe fused bicyclic pyrimidine derivative according to claim 1, or a saltthereof.
 14. An NK1 receptor antagonist containing as an activeingredient the fused bicyclic pyrimidine derivative according to claim1, or a salt thereof.
 15. A prophylactic or therapeutic agent fordysuria, including defective bladder functions such as increased urinaryfrequency and incontinence of urine, containing as an active ingredientthe fused bicyclic pyrimidine derivative according to claim 1, or a saltthereof.
 16. A prophylactic or therapeutic agent for disorders ofdigestive tract such as ulcerative colitis and Crohn's disease,containing as an active ingredient the fused bicyclic pyrimidinederivative according to claim 1, or a salt thereof.
 17. A prophylacticor therapeutic agent for vomiting induced by exposure to X-ray,chemotherapy, pregnancy, migraine, postoperative pains, decreasedgastrointestinal motility, and side effects of drugs, containing as anactive ingredient the fused bicyclic pyrimidine derivative according toclaim 1, or a salt thereof.
 18. A therapeutic agent for treatingconditions, such as asthma, coughing, ache, migraine, tooth pain, andrheumatoid arthritis, containing as an active ingredient the fusedbicyclic pyrimidine derivative according to claim 1, or a salt thereof.